Bicyclic heterocycles as fgfr4 inhibitors

ABSTRACT

The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR4 enzyme and are useful in the treatment of FGFR4-associated diseases such as cancer.

FIELD OF THE INVENTION

The present disclosure relates to bicyclic heterocycles, andpharmaceutical compositions of the same, that are inhibitors of theenzyme FGFR4 and are useful in the treatment of FGFR4-associateddiseases such as cancer.

BACKGROUND OF INVENTION

The Fibroblast Growth Factor Receptors (FGFR) are receptor tyrosinekinases that bind to fibroblast growth factor (FGF) ligands. There arefour FGFR proteins (FGFR1-4) that are capable of binding ligands and areinvolved in the regulation of many physiological processes includingtissue development, angiogenesis, wound healing, and metabolicregulation. Upon ligand binding, the receptors undergo dimerization andphosphorylation leading to stimulation of the protein kinase activityand recruitment of many intracellular docking proteins. Theseinteractions facilitate the activation of an array of intracellularsignaling pathways including Ras-MAPK, AKT-PI3K, and phospholipase Cthat are important for cellular growth, proliferation and survival(Reviewed in Eswarakumar et al. Cytokine & Growth Factor Reviews, 2005).

Aberrant activation of this pathway either through overexpression of FGFligands or FGFR or activating mutations in the FGFRs can lead to tumordevelopment, progression, and resistance to conventional cancertherapies. In human cancer, genetic alterations including geneamplification, chromosomal translocations and somatic mutations thatlead to ligand-independent receptor activation have been described.Large scale DNA sequencing of thousands of tumor samples has revealedthat components of the FGFR pathway are among the most frequentlymutated in human cancer. Many of these activating mutations areidentical to germline mutations that lead to skeletal dysplasiasyndromes. Mechanisms that lead to aberrant ligand-dependent signalingin human disease include overexpression of FGFs and changes in FGFRsplicing that lead to receptors with more promiscuous ligand bindingabilities (Reviewed in Knights and Cook Pharmacology & Therapeutics,2010; Turner and Grose, Nature Reviews Cancer, 2010). Therefore,development of inhibitors targeting FGFR may be useful in the clinicaltreatment of diseases that have elevated FGF or FGFR activity.

The cancer types in which FGF/FGFRs are implicated include, but are notlimited to: carcinomas (e.g., bladder, breast, cervical, colorectal,endometrial, gastric, head and neck, kidney, liver, lung, ovarian,prostate); hematopoietic malignancies (e.g., multiple myeloma, chroniclymphocytic lymphoma, adult T cell leukemia, acute myelogenous leukemia,non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenstrom'sMacroglubulinemia); and other neoplasms (e.g., glioblastoma, melanoma,and rhabdosarcoma). In addition to a role in oncogenic neoplasms, FGFRactivation has also been implicated in skeletal and chondrocytedisorders including, but not limited to, achrondroplasia andcraniosynostosis syndromes.

The FGFR4-FGF19 signaling axis, specifically, has been implicated in thepathogenesis of a number of cancers including hepatocellular carcinoma(Heinzle et al., Cur. Pharm. Des. 2014, 20:2881). Ectopic expression ofFGF19 in transgenic mice was shown to lead to tumor formation in theliver and a neutralizing antibody to FGF19 was found to inhibit tumorgrowth in mice. In addition, overexpression of FGFR4 has been observedin a multiple tumor types including hepatocellular carcinoma,colorectal, breast, pancreatic, prostate, lung, and thyroid cancers.Furthermore, activating mutations in FGFR4 have been reported inrhabdomyosarcoma (Taylor et al. JCI 2009,119:3395). Targeting FGFR4 withselective small molecule inhibitors may therefore prove beneficial inthe treatment of certain cancers.

There is a continuing need for the development of new drugs for thetreatment of cancer and other diseases, and the FGFR4 inhibitorsdescribed herein help address this need.

SUMMARY OF INVENTION

The present disclosure is directed to inhibitors of FGFR4 having Formula(I):

or pharmaceutically acceptable salts thereof, wherein constituentvariables are defined herein.

The present disclosure is further directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.

The present disclosure is further directed to methods of inhibiting anFGFR4 enzyme comprising contacting the enzyme with a compound of Formula(I), or a pharmaceutically acceptable salt thereof.

The present disclosure is further directed to a method of treating adisease associated with abnormal activity or expression of an FGFR4enzyme, comprising administering a compound of Formula (I), or apharmaceutically acceptable salt thereof, to a patient in need thereof.

The present disclosure is further directed to compounds of Formula (I)for use in treating a disease associated with abnormal activity orexpression of an FGFR4 enzyme.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR4 enzyme, or a mutant thereof, in a patientin need thereof, comprising the step of administering to said patient acompound according to the present invention or pharmaceuticallyacceptable composition thereof.

The present disclosure is further directed to a method for treating adisorder mediated by an FGFR4 enzyme, or a mutant thereof, in a patientin need thereof, comprising the step of administering to the patient acompound according to the present invention or a pharmaceuticallyacceptable salt thereof, or a composition comprising a compoundaccording to the present invention, in combination with another therapyor therapeutic agent as described herein.

The present disclosure is further directed to the use of compounds ofFormula (I) in the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION Compounds

In one aspect, the present disclosure provides compounds of Formula (I):

or pharmaceutically acceptable salts thereof, wherein:

X¹ is CR¹⁰R¹¹ orNR⁷;

X is N or CR⁶;

R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁶ and R⁷ are each independently selected from H, halo, CN, OR^(a4),SR^(a4), C(O)NR^(c4)R^(d4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4),NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆cycloalkyl, a 5-6 membered heteroaryl having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R⁶ and R⁷ are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(10A);

L is —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independenently H,C₁₋₆ alkyl, C₆₋₁₀ aryl, 5 to 10 membered heteroaryl or 4 to 7 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, 5 to 10 memberedheteroaryl or 4 to 7-membered heterocycloalkyl is optionally substitutedwith from 1 to 3 R¹⁷ groups; or R¹³ and R¹⁴ are taken together with thecarbon atom to which they are attached form a C₃₋₆ cycloalkyl or 4 to6-membered heterocycloalkyl group; wherein the C₃₋₆ cycloalkyl or 4 to6-membered heterocycloalkyl group is optionally substituted with from 1to 3 R¹⁷ members; the subscript n is 1, 2 or 3; in some embodiments, thesubscript n is 1 or 2.

R⁸ is H or C₁₋₄ alkyl which is optionally substituted by halo, CN,OR^(a9), C(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), phenyl, C₃₋₇cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, or a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R⁸ are each optionally substituted with 1 or 2 R¹⁹;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, a5-10 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-10 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl groups of R¹⁰ and R¹¹ areeach optionally substituted with 1, 2, 3, or 4 R^(10A);

R^(10A), at each occurrence, is independently selected from halo, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

R^(a4), R^(b4), R^(c4), and R^(d4), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroup of R^(a4), R^(b4), R^(c4), and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

each R^(e4) is independently H or C₁₋₄ alkyl;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

R¹² is H or C₁₋₄ alkyl which is optionally substituted by R¹⁷;

R¹⁷, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R¹⁷ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

R^(a7), R^(b7), R^(c7), and R^(d7), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R^(a7), R^(b7), R^(c7), and R^(d7) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

alternatively, R^(c7) and R^(d7) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

R^(e7), at each occurrence, is independently H or C₁₋₄ alkyl;

R¹⁹, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),OC(O)R^(b9), OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl;

R^(a9), R^(c9), and R^(d9), at each occurrence, are independentlyselected from H and C₁₋₄ alkyl; and

R^(b9), at each occurrence, is independently C₁₋₄ alkyl. In oneembodiment, Y is O. In another embodiment, Y is NR⁸.

In some embodiments of compounds of Formula (I):

X¹ is CR¹⁰R¹¹ or NR⁷;

X is N or CR⁶;

R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁶is selected fromH, halo, CN, OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R⁶ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(10A);

R⁷ is selected from H, C(O)NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4),S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylhaving carbon and 1, 2, or 3 heteroatoms independently selected from N,O and S, and a 4-7 membered heterocycloalkyl moiety having carbon and 1,2, or 3 heteroatoms independently selected from N, O and S; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6membered heteroaryl, and 4-7 membered heterocycloalkyl groups of R⁷ areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R^(10A);

L is —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independently H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5 to 10 membered heteroaryl or 4 to 10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, 5 to 10 memberedheteroaryl or 4 to 7 membered heterocycloalkyl is optionally substitutedwith from 1 to 3 R¹⁷ groups;

the subscript n is 1 or 2;

R⁸ is H or C₁₋₄ alkyl which is optionally substituted by halo, CN,OR^(a9), C(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), phenyl, C₃₋₇cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, or a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R⁸ are each optionally substituted with 1 or 2 R¹⁹;

R¹⁰ and R¹¹ are each independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, a5-10 membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-10 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl groups of R¹⁰ and R¹¹ areeach optionally substituted with 1, 2, 3, or 4 R^(10A);

R^(10A), at each occurrence, is independently selected from halo, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

R^(a4), R^(b4), R^(c4), and R^(d4), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroup of R^(a4), R^(b4), R^(c4), and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

R^(e4), at each occurrence, is H or C₁₋₄ alkyl;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

R¹² is H or C₁₋₄ alkyl which is optionally substituted by R¹⁷;

R¹⁷, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R¹⁷ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

R^(a7), R^(b7), R^(c7), and R^(d7), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R^(a7), R^(b7), R^(c7), and R^(d7) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

alternatively, R^(c7) and R^(d7) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

R^(e7), at each occurrence, is independently H or C₁₋₄ alkyl;

R¹⁹, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),OC(O)R^(b9), OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl;

R^(a9), R^(c9), and R^(d9), at each occurrence, are independentlyselected from H and C₁₋₄ alkyl; and

R^(b9), at each occurrence, is independently C₁₋₄ alkyl.

In some embodiments of compound of Formula (I), R⁷ is selected from H,C(O)NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroaryl havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS, and a 4-7 membered heterocycloalkyl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 memberedheteroaryl, and 4-7 membered heterocycloalkyl groups of R⁷ are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R^(10A).

In some embodiments of compounds of Formula (I), the present disclosureprovides an inhibitor of FGFR4, which is a compound having Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

X is N or CR⁶;

R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R² is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R³ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁴ is C₁₋₃ alkyl or C₁₋₃ haloalkyl;

R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy;

R⁶is H, halo, CN, OR^(a4), SR^(a4), C(O)NR^(c4)R^(d4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R⁶ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(10A);

L is —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independently H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5 to 10 membered heteroaryl or 4 to 10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, 5 to 10 memberedheteroaryl or 4 to 10 membered heterocycloalkyl is optionallysubstituted with from 1 to 3 R¹⁷ groupswherein each R¹⁷ member isoptionally substituted with from 1-3 R¹⁹ members; the subscript n is 1,2 or 3;

R⁸ is H or C₁₋₄ alkyl which is optionally substituted by halo, CN,OR^(a9), C(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), phenyl, C₃₋₇cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, or a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R⁸ are each optionally substituted with 1 or 2 R¹⁹;

R¹⁰ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, a 5-10 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-10 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylgroups of R¹⁰ are each optionally substituted with 1, 2, 3, or 4R^(10A);

R^(10A), at each occurrence, is independently selected from halo, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

R^(a4), R^(b4), R^(c4), and R^(d4), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroup of R^(a4), R^(b4), R^(c4), and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

R^(e4) is H or C₁₋₄ alkyl;

R¹¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areeach optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹⁹;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group; whereinsaid 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, 7-,8-, 9-, or 10-membered heterocycloalkyl group are each optionallysubstituted with 1, 2, 3 or 4 R^(10A);

R¹² is H or C₁₋₄ alkyl which is optionally substituted by R¹⁷;

R¹⁷, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R¹⁷ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

R^(a7), R^(b7), R^(c7), and R^(d7), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R^(a7), R^(b7), R^(c7), and R^(d7) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

alternatively, R^(c7) and R^(d7) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹;

R^(e7), at each occurrence, is H or C₁₋₄ alkyl;

R¹⁹, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),OC(O)R^(b9), OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl;

R^(a9), R^(c9), and R^(d9), at each occurrence, are independentlyselected from H and C₁₋₄ alkyl; and

R^(b9), at each occurrence, is C₁₋₄ alkyl.

In some embodiments of compounds of Formula (I), the present disclosureprovides compounds or pharmaceutically acceptable salts thereof, whichare FGFR4 inhibitors and have Formula (III):

The variables R¹, R², R³, R⁴, R⁵, R¹⁰, R¹¹, R¹², X and L are as definedin any embodiment of compound of Formula (I).

In some embodiments of compounds of Formula (I), the present disclosureprovides compounds, or pharmaceutically acceptable salts threof, whichare FGFR4 inhibitors and have Formula (IV):

The variables R¹, R², R³, R⁴, R⁵, R¹⁰, R¹¹, R¹², X and n are as definedin any embodiment of compound of Formula (I).

In some embodiments of compounds of Formula (I), the present disclosureprovides compounds of Formula (V) or pharmaceutically acceptable saltsthereof, which have FGFR4 inhibitory activities.

In some embodiments of compounds of Formula (V), R¹⁰ and R¹¹ are takentogether with the carbon atom to which they are attached form C₃₋₆cycloalkyl, optionally substituted with 1 or 2 R^(10A) groups.

In certain embodiments of compounds of Formula (I), R¹⁰ and R¹¹ togetherwith the carbon atom to which they are attached form a cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl group. In one embodiment, X is CH.In another embodiement, X is N.

In some embodiments of compounds of Formula (I), the present disclosureprovides compounds of Formula (VI) or pharmaceutically acceptable saltsthereof, which have FGFR4 inhibitory activities.

In some embodiments of compounds of Formula (VI), R⁷ is C₁₋₆ alkyl,phenyl, 5- or 6-membered heteroaryl, C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl, each of which is optionally substituted with from 1-2members selected from halo, C₁₋₄ alkyl, CN, C₁₋₄ haloalkyl, C₁₋₄ alkoxy,phenyl, C₃₋₆ cycloalkyl, 5- or 6-membered heteroaryl, C₃₋₆ cycloalkyl or4- to 6-membered heterocycloalkyl.

In certain embodiments of compounds of Formula (I), R⁷ is methyl, ethyl,isopropyl, n-butyl, cyanomethyl, 2,2,2-trifluoroethyl, phenyl,3-pyridyl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl,tetrahydrofuran-3-yl, 3,3-difluorocyclobutyl, 2-methoxyethyl,cyclopropylmethyl, 2,2-difluoroethyl, benzyl, 3-fluorobenzyl,pyridin-3-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl,(1-methyl-1H-pyrazol-3-yl)methyl or (teterahydrofuranyl-3-yl)methyl. Inone embodiment, X is CH. In another embodiement, X is N.

In some embodiments the present disclosure provides inhibitors of FGFR4having Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

R² is F or Cl;

R⁵ is F or Cl;

L is —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independenently H,C₁₋₆ alkyl or C₆₋₁₀ aryl, wherein the C₁₋₆ alkyl or C₆₋₁₀ aryl isoptionally substituted with from 1 to 3 R¹⁷ groups; or R¹³ and R¹⁴ aretaken together with the carbon atom to which they are attached form aC₃₋₆ cycloalkyl or 4 to 6-membered heterocycloalkyl group; wherein theC₃₋₆ cycloalkyl or 4 to 6-membered heterocycloalkyl group is optionallysubstituted with from 1 to 3 R¹⁷;

R⁸ is H or methyl;

R¹⁰ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, a 5-10 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-10 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkylgroups of R¹⁰ are each optionally substituted with 1, 2, 3, or 4R^(10A);

R^(10A), at each occurrence, is independently selected from halo, CN,NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R^(10a) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

R^(a4), R^(b4), R^(c4), and R^(d4), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety comprisingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R^(a4), R^(b4), R^(c4), and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹;

alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents s independently selected from R¹⁹;

R^(e4), at each occurrence, is independently H or C₁₋₄ alkyl;

R¹¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

alternatively, R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group or a4-, 5-, 6-, or 7-membered heterocycloalkyl group; wherein said 3-, 4-,5-, 6-, or 7-membered cycloalkyl group and 4-, 5-, 6-, or 7-memberedheterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4R^(10A);

R¹⁷, at each occurrence, is independently selected from OH, CN, amino,halo, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

R¹⁹, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9),OC(O)R^(b9), OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl;

R^(a9), R^(c9), and R^(d9), at each occurrence, are independentlyselected from H and C₁₋₄ alkyl; and

R^(b9), at each occurrence, is independently C₁₋₄ alkyl.

In some embodiments of compounds of Formula (Ia) as described above, Lis —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independently H, C₁₋₆alkyl, and C₆₋₁₀ aryl, wherein the C₁₋₆ alkyl and C₆₋₁₀ aryl isoptionally substituted with from 1 to 3 independently selected R¹⁷groups.

In some embodiments, X is N.

In some embodiments, X is CR⁶.

In some embodiments, R⁶ is H, halo, CN, or C₁₋₆ alkyl. In someembodiments, R⁶ is H. In some embodiments, R⁶ is C₁₋₆ alkyl. In someembodiments, R⁶ is methyl. In some embodiments, R⁶ is halo. In someembodiments, R⁶ is CN.

In some embodiments, R¹ is C₁₋₃ alkyl. In some embodiments, R¹ ismethyl.

In some embodiments, R² is halo. In some embodiments, R² is fluoro. Insome embodiments, R² is chloro.

In some embodiments, R³ is H.

In some embodiments, R⁴ is C₁₋₃ alkyl. In some embodiments, R⁴ ismethyl.

In some embodiments, R⁵ is halo. In some embodiments, R⁵ is fluoro. Insome embodiments, R⁵ is chloro.

In some embodiments, R² is fluoro and R⁵ is fluoro. In some embodiments,R² is chloro and R⁵ is chloro.

In some embodiments, R⁷ is C₁₋₆ alkyl, phenyl, 5- or 6-memberedheteroaryl, C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkyl, eachof which is optionally substituted with from 1-2 members selected fromhalo, C₁₋₄ alkyl, CN, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, phenyl, C₃₋₆cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-memberedheterocycloalkyl.

In some embodiments, R⁷ is methyl, ethyl, propyl, isopropyl, n-butyl,cyanomethyl, 2,2,2-trifluoroethyl, phenyl, 3-pyridyl,1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl,tetrahydrofuran-3-yl, 3,3-difluorocyclobutyl, 2-methoxyethyl,cyclopropyl, cyclopropylmethyl, 2,2-difluoroethyl, benzyl,3-fluorobenzyl, pyridin-3-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl,(1-methyl-1H-pyrazol-3-yl)methyl, (teterahydrofuranyl-3-yl)methyl,2-fluoroethyl, 4-pyridyl, (piperidin-4-yl)methyl,(1-methylpiperidin-4-yl)methyl, (1-methoxycarbonylpiperidin-4-yl)methyl,(1-methylsulfonylpiperidin-4-yl)methyl, tetrahydropyran-4-yl,cyclobutyl, cyclopentyl, isobutyl, 1-(cyclobutylmethyl), or4-methyl-N-isopropylpiperidine-1-carboxamide.

In some embodiments, R⁷ is methyl, ethyl, propyl, isopropyl, n-butyl,cyanomethyl, 2,2,2-trifluoroethyl, phenyl, 3-pyridyl,1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl,tetrahydrofuran-3-yl, 3,3-difluorocyclobutyl, 2-methoxy ethyl,cyclopropyl, cyclopropylmethyl, 2,2-difluoroethyl, benzyl,3-fluorobenzyl, pyridin-3-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl,(1-methyl-1H-pyrazol-3-yl)methyl or (teterahydrofuranyl-3-yl)methyl.

In some embodiments, R⁷ is ethyl, propyl, isopropyl, cyanomethyl,2,2,2-trifluoroethyl, 2,2-difluoroethyl, phenyl, 3-pyridyl,1-methyl-1H-pyrazol-3-yl, tetrahydrofuran-3-yl, 3,3-difluorocyclobutyl,2-methoxy ethyl, cyclopropyl, cyclopropylmethyl, 3-fluorobenzyl,pyridin-3-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl, or(teterahydrofuranyl-3-yl)methyl.

In some embodiments, R⁷ is 2-fluoroethyl, 4-pyridyl,(piperidin-4-yl)methyl, (1-methylpiperidin-4-yl)methyl,(1-methoxycarbonylpiperidin-4-yl)methyl,(1-methylsulfonylpiperidin-4-yl)methyl, tetrahydropyran-4-yl,cyclobutyl, cyclopentyl, isobutyl, 1-(cyclobutylmethyl), or4-methyl-N-isopropylpiperidine-1-carboxamide.

In some embodiments, R¹ is C₁₋₃ alkyl; R² is halo; R³ is H; R⁴ is C₁₋₃alkyl; and R⁵ is halo.

In some embodiments, R¹ is C₁₋₃ alkyl; R² is F; R³ is H; R⁴ is C₁₋₃alkyl; and R⁵ is F.

In some embodiments, R¹ is methyl; R² is F; R³ is H; R⁴ is methyl; andR⁵ is F.

In some embodiments, R¹ is C₁₋₃ alkyl; R² is Cl; R³ is H; R⁴ is C₁₋₃alkyl; and R⁵ is Cl.

In some embodiments, R¹ is methyl; R² is Cl; R³ is H; R⁴ is methyl; andR⁵ is Cl.

In some embodiments, R¹⁰ is C₁₋₆ alkyl. In some embodiments, R¹⁰ ismethyl.

In some embodiments, R¹¹ is C₁₋₆ alkyl. In some embodiments, R¹¹ ismethyl.

In some embodiments, R¹⁰ and R¹¹ are each C₁₋₆ alkyl. In someembodiments, R¹⁰ and R¹¹ are each methyl.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl group.In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a 3-, 4-, 5-, or 6-membered cycloalkyl group. Insome embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a 3-, 4-, or 5-membered cycloalkyl group.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl group. In some embodiments, R¹⁰ andR¹¹ together with the carbon atom to which they are attached form acyclobutyl group. In some embodiments, R¹⁰ and R¹¹ together with thecarbon atom to which they are attached form a cyclopentyl group. In someembodiments, R¹⁰ and R¹¹ together with the carbon atom to which they areattached form a cyclohexyl group. In some embodiments, R¹⁰ and R¹¹together with the carbon atom to which they are attached form acycloheptyl group.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl group optionally substituted by 1or 2 R^(10A). In some embodiments, R¹⁰ and R¹¹ together with the carbonatom to which they are attached form a cyclobutyl group optionallysubstituted by 1 or 2 R^(10A). In some embodiments, R¹⁰ and R¹¹ togetherwith the carbon atom to which they are attached form a cyclopentyl groupoptionally substituted by 1 or 2 R^(10A). In some embodiments, R¹⁰ andR¹¹ together with the carbon atom to which they are attached form acyclohexyl group optionally substituted by 1 or 2 R^(10A).

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl group.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a cyclopropyl or cyclopentyl group.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup.

In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a tetrahydropyranyl group (e.g.,2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl), atetrahydrofuranyl group (e.g., 2-tetrahydrofuranyl or3-tetrahydrofuranyl) , tetrahydrothiophenyl group (e.g.,2-tetrahydrothiophenyl or 3-tetrahydrothiophenyl) , a pyrrolidinyl group(e.g., 2-pyrrolidinyl or 3-pyrrolidinyl), a piperidinyl group (e.g.,2-piperidinyl, 3-piperidinyl or 4-piperidinyl), 2-morpholinyl or3-morpholinyl, each of which is optionally substituted with 1 or 2R^(10A) groups. In some embodiments, R¹⁰ and R¹¹ together with thecarbon atom to which they are attached form a tetrahydropyranyl group.In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a tetrahydropyranyl group optionally substitutedby 1 or 2 R^(10A). In some embodiments, R¹⁰ and R¹¹ together with thecarbon atom to which they are attached form a tetrahydrofuranyl group.In some embodiments, R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form a tetrahydrofuranyl group optionally substitutedby R^(10A). In some embodiments, R¹⁰ and R¹¹ together with the carbonatom to which they are attached form an azetidinyl group. In someembodiments, R¹⁰ and R¹¹ together with the carbon atom to which they areattached form an azetidinyl group optionally substituted by R^(10A).

In some embodiments, L is —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are eachindependently H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl or4-10 membered heterocycloalkyl, each of which is optionally substitutedwith from 1-3 R¹⁷ groups; and n is 1 or 2. In some embodiments, L is—(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independently H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl.

In some embodiments, L is —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are eachindependently H or R¹³ and R¹⁴ taken together with the carbon atom towhich they are attached form a 3 to 6 membered cycloalkyl group or 4 to7-membered heterocycloalkyl group, where the 3 to 6 membered cycloalkylgroup or 4 to 7-membered heterocycloalkyl group is optionallysubstituted with from 1 or 2 R¹⁷ groups. In some embodiments, L is—(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independently H or R¹³ andR¹⁴ taken together with the carbon atom to which they are attached forma 3 to 6 membered cycloalkyl group or 4 to 7-membered heterocycloalkylgroup.

In some embodiments, L is —CH₂C(R¹³)(R¹⁴)— or —C(R¹³)(R¹⁴)CH₂—, whereR¹³ and R¹⁴ taken together with the carbon atom to which they areattached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group,each of which is optionally substituted with 1 or 2 R¹⁷ groups. In someembodiments, L is —CH₂C(R¹³)(R¹⁴)— or —C(R¹³)(R¹⁴)CH₂—, where R¹³ andR¹⁴ taken together with the carbon atom to which they are attached formcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

In some embodiments, L is —CH₂C(R¹³)(R¹⁴)— or —C(R¹³)(R¹⁴)CH₂—, whereR¹³ and R¹⁴ taken together with the carbon atom to which they areattached form a tetrahydropyranyl group (e.g., 2-tetrahydropyranyl,3-tetrahydropyranyl or 4-tetrahydropyranyl), a tetrahydrofuranyl group(e.g., 2-tetrahydrofuranyl or 3-tetrahydrofuranyl), tetrahydrothiophenylgroup (e.g., 2-tetrahydrothiophenyl or 3-tetrahydrothiophenyl), apyrrolidinyl group (e.g., 2-pyrrolidinyl or 3-pyrrolidinyl), apiperidinyl group (e.g., 2-piperidinyl, 3-piperidinyl or 4-piperidinyl),2-morpholinyl or 3-morpholinyl, each of which is optionally substitutedwith 1 or 2 R¹⁷ groups. In some embodiments, L is —CH₂C(R¹³)(R¹⁴)— or—C(R¹³)(R¹⁴)CH₂—, where R¹³ and R¹⁴ taken together with the carbon atomto which they are attached form a tetrahydropyranyl group (e.g.,2-tetrahydropyranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl), atetrahydrofuranyl group (e.g., 2-tetrahydrofuranyl or3-tetrahydrofuranyl), tetrahydrothiophenyl group (e.g.,2-tetrahydrothiophenyl or 3-tetrahydrothiophenyl), a pyrrolidinyl group(e.g., 2-pyrrolidinyl or 3-pyrrolidinyl), a piperidinyl group (e.g.,2-piperidinyl, 3-piperidinyl or 4-piperidinyl), 2-morpholinyl or3-morpholinyl.

In some embodiments, L is —(CH₂)_(n)—, where n is 1, 2 or 3. In oneembodiment, L is CH₂.

In some embodiments, L is —(CH₂)_(n)—, where n is 1 or 2.

In a preferred embodiment, R⁸ is H. In another preferred embodiment, R¹²is H. In another preferred embodiment, X is CH. In another preferredembodiment, X is N.

In some embodiments, R¹⁷ is methyl.

In some embodiments, R⁸ is H or C₁₋₄ alkyl. In some embodiments, R⁸ is Hor methyl. In some embodiments, R⁸ is H. In some embodiments, R⁸ ismethyl.

In some embodiments, R¹² is H or C₁₋₄ alkyl which is optionallysubstituted by R¹⁷; wherein R¹⁷, at each occurrence, is independentlyselected from halo, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7),NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7),S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, and C₁₋₄ haloalkyl.

In some embodiments, R^(a7), R^(c7), and R^(d7), at each occurrence, areindependently selected from H and C₁₋₄ alkyl; and each R^(b7) isindependently C₁₋₄ alkyl.

In some embodiments, R¹² is H or C₁₋₄ alkyl. In some embodiments, R¹² isC₁₋₄ alkyl. In some embodiments, R¹² is C₁₋₄ alkyl substituted by—N(CH₃)₂. In some embodiments, R¹² is —CH₂—N(CH₃)₂. In some embodiments,R¹² is methyl. In some embodiments, R¹² is C₁₋₄ alkyl substituted bypiperidin-1-yl. In some embodiments, R¹² is —CH₂(piperidin-1-yl).

In some embodiments, R¹² is H.

In some embodiments, the present disclosure provides an inhibitor ofFGFR4 which is a compound having Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein X, L, R¹, R², R³,R⁴, R⁵, R⁸, R¹⁰, R¹¹, and R¹² are as defined herein; R^(12a) is H; andR^(12b) is H.

In some embodiments the present invention is an inhibitor of FGFR4 whichis a compound having Formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein L, R², R⁵, R⁸,R¹⁰, R¹¹, and R¹² are as defined herein; R^(12a) is H; and R^(12b) is H.

In some embodiments, R^(12a) is H, F, methyl, or trifluoromethyl.

In some embodiments, R^(12b) is H, F, methyl, or trifluoromethyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

At various places in the present specification various aryl, heteroaryl,cycloalkyl, and heterocycloalkyl rings are described. Unless otherwisespecified, these rings can be attached to the rest of the molecule atany ring member as permitted by valency. For example, the term “apyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyridin-3-yl,or pyridin-4-yl ring.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety independently selectedfrom the group defining the variable. For example, where a structure isdescribed having two R groups that are simultaneously present on thesame compound, the two R groups can represent different moietiesindependently selected from the group defined for R.

Definitions

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted.

As used herein, the term “substituted” means that a hydrogen atom isreplaced by a non-hydrogen group. It is to be understood thatsubstitution at a given atom is limited by valency.

As used herein, the term “C_(i-j),” where i and j are integers, employedin combination with a chemical group, designates a range of the numberof carbon atoms in the chemical group with i-j defining the range. Forexample, C₁₋₆ alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6carbon atoms.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyltert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl, and the like. In some embodiments, the alkylgroup is methyl, ethyl, or propyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, means a saturated divalent linkinghydrocarbon group that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkylene group contains from 1 to 4carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.Examples of alkylene moieties include, but are not limited to, chemicalgroups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene,1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

As used herein, “alkenyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon doublebonds. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkenyl groups include, but are not limited to,ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “alkynyl,” employed alone or in combination with otherterms, refers to an alkyl group having one or more carbon-carbon triplebonds. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4carbon atoms. Example alkynyl groups include, but are not limited to,ethynyl, propyn-1-yl, propyn-2-yl, and the like.

As used herein, “halo” or “halogen”, employed alone or in combinationwith other terms, includes fluoro, chloro, bromo, and iodo. In someembodiments, halo is F or Cl. In some embodiments, halo is F.

As used herein, the term “haloalkyl,” employed alone or in combinationwith other terms, refers to an alkyl group having up to the full valencyof halogen atom substituents, which may either be the same or different.In some embodiments, the halogen atoms are fluoro atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅,and the like.

As used herein, the term “alkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-alkyl. In some embodiments,the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examplealkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like. In some embodiments, alkoxy ismethoxy.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-(haloalkyl). In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.An example haloalkoxy group is —OCF₃.

As used herein, “amino,” employed alone or in combination with otherterms, refers to NH₂.

As used herein, the term “alkylamino,” employed alone or in combinationwith other terms, refers to a group of formula —NH(alkyl). In someembodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms.Example alkylamino groups include methylamino, ethylamino, propylamino(e.g., n-propylamino and isopropylamino), and the like.

As used herein, the term “dialkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂.Example dialkylamino groups include dimethylamino, diethylamino,dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and thelike. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms.

As used herein, the term “alkylthio,” employed alone or in combinationwith other terms, refers to a group of formula —S-alkyl. In someembodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a non-aromatic cyclic hydrocarbon includingcyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono-or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings)ring systems. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings (e.g., aryl or heteroaryl rings)fused (i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo derivatives of cyclopentane, cyclohexene, cyclohexane,and the like, or pyrido derivatives of cyclopentane or cyclohexane.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo. Cycloalkyl groups also include cycloalkylidenes. Theterm “cycloalkyl” also includes bridgehead cycloalkyl groups (e.g.,non-aromatic cyclic hydrocarbon moieties containing at least onebridgehead carbon, such as admantan-1-yl) and spirocycloalkyl groups(e.g., non-aromatic hydrocarbon moieties containing at least two ringsfused at a single carbon atom, such as spiro[2.5]octane and the like).In some embodiments, the cycloalkyl group has 3 to 10 ring members, or 3to 7 ring members, or 3 to 6 ring members. In some embodiments, thecycloalkyl group is monocyclic or bicyclic. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is a C₃₋₇ monocyclic cycloalkyl group. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, tetrahydronaphthalenyl,octahydronaphthalenyl, indanyl, and the like. In some embodiments, thecycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic ring or ringsystem, which may optionally contain one or more alkenylene oralkynylene groups as part of the ring structure, which has at least oneheteroatom ring member independently selected from nitrogen, sulfur,oxygen, and phosphorus. Heterocycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused, bridged, or spiro rings) ringsystems. In some embodiments, the heterocycloalkyl group is a monocyclicor bicyclic group having 1, 2, 3, or 4 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having abond in common with) to the non-aromatic heterocycloalkyl ring, forexample, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkylgroups can also include bridgehead heterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least one bridgehead atom, such asazaadmantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., aheterocycloalkyl moiety containing at least two rings fused at a singleatom, such as [1,4-dioxa-8-aza-spiro[4.5]decan-N-yl] and the like). Insome embodiments, the heterocycloalkyl group has 3 to 10 ring-formingatoms, 4 to 10 ring-forming atoms, or 3 to 8 ring forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atomsor heteroatoms in the ring(s) of the heterocycloalkyl group can beoxidized to form a carbonyl, an N-oxide, or a sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. In someembodiments, the heterocycloalkyl portion is a C₂₋₇ monocyclicheterocycloalkyl group. In some embodiments, the heterocycloalkyl groupis a morpholine ring, pyrrolidine ring, piperazine ring, piperidinering, dihydropyran ring, tetrahydropyran ring, tetrahyropyridine,azetidine ring, or tetrahydrofuran ring. In some embodiments, theheterocycloalkyl is a 4-7 membered heterocycloalkyl moiety having carbonand 1, 2, or 3 heteroatoms independently selected from N, O and S. Insome embodiments, the heterocycloalkyl is 4-10 membered heterocycloalkylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2 fusedrings) aromatic hydrocarbon moiety, such as, but not limited to, phenyl,1-naphthyl, 2-naphthyl, and the like. In some embodiments, aryl groupshave from 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments,the aryl group is a monocyclic or bicyclic group. In some embodiments,the aryl group is phenyl or naphthyl.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2or 3 fused rings) aromatic hydrocarbon moiety, having one or moreheteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl group is a monocyclic orbicyclic group having 1, 2, 3, or 4 heteroatoms independently selectedfrom nitrogen, sulfur and oxygen. Example heteroaryl groups include, butare not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyrrolyl,azolyl, quinolinyl, isoquinolinyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl or the like. The carbon atoms or heteroatoms inthe ring(s) of the heteroaryl group can be oxidized to form a carbonyl,an N-oxide, or a sulfonyl group (or other oxidized linkage) or anitrogen atom can be quaternized, provided the aromatic nature of thering is preserved. In one embodiment the heteroaryl group is a 5 to 10membered heteroaryl group. In another embodiment the heteroaryl group isa 5 to 6 membered heteroaryl group. In some embodiments, the heteroarylis a 5-6 membered heteroaryl moiety having carbon and 1, 2, or 3heteroatoms independently selected from N, O and S. In some embodiments,the heteroaryl is a 5-10 membered heteroaryl moiety having carbon and 1,2, or 3 heteroatoms independently selected from N, O and S.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out bymethods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids. Other resolvingagents suitable for fractional crystallization methods includestereoisomerically pure forms of methylbenzylamine (e.g., S and R forms,or diastereomerically pure forms), 2-phenylglycinol, norephedrine,ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention also include all isotopes of atoms occurringin the intermediates or final compounds. Isotopes include those atomshaving the same atomic number but different mass numbers. For example,isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%), or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the non-toxic salts ofthe parent compound formed, for example, from non-toxic inorganic ororganic acids. The pharmaceutically acceptable salts of the presentinvention can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g.,methanol, ethanol, iso-propanol, orbutanol) or acetonitrile (ACN) arepreferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The following abbreviations may be used herein: AcOH (acetic acid); AC₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); br (broad); Cbz (carboxybenzyl); calc. (calculated);d (doublet); dd (doublet of doublets); DCM (dichloromethane); DEAD(diethyl azodicarboxylate); DIAD (N,N′-diisopropyl azidodicarboxylate);DIPEA (N,N-diisopropylethylarnine); DMF (N,N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU(N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquidchromatography-mass spectrometry); m (multiplet); M (molar); wCPBA(3-chloroperoxybenzoic acid); MgSO₄ (magnesium sulfate); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); NaHCO₃ (sodium bicarbonate); NaOH (sodiumhydroxide); Na₂SO₄ (sodium sulfate); NH₄Cl (ammonium chloride); NH₄OH(ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonancespectroscopy); OTf (trifluoromethanesulfonate); Pd (palladium); Ph(phenyl); pM (picomolar); PMB (para-methoxybenzyl), POCl₃ (phosphorylchloride); RP-HPLC (reverse phase high performance liquidchromatography); s (singlet); t (triplet or tertiary); TBS(tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets);t-Bu (fert-butyl); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg(microgram(s)); μL (microliter(s)); μM (micromolar); wt % (weightpercent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and according to variouspossible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), ormass spectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

The expressions, “ambient temperature,” “room temperature,” and “r.t.”,as used herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

Compounds of the invention can be prepared by one skilled in the artaccording to preparatory routes known in the literature. Examplesynthetic methods for preparing compounds of the invention are providedin the Schemes below.

Compounds of formula 4 can be synthesized using procedures as outlinedin Scheme 1. Reduction of ester 1 using diisobutylaluminium hydride(DIBAL-H) can afford the corresponding aldehyde 2. Reductive aminationof aldehyde 2 with aniline 3 using a suitable reducing agent such assodium triacetoxyborohydride [Na(OAc)₃BH] in the presence of an acidsuch as acetic acid or trifluoroacetic acid (TFA) can afford the amineof formula 4.

The substituted dichloropyrimidine of formula 8 can be prepared by themethod described in Scheme 2. Treatment of the commercially available5-(chloromethyl)pyrimidine-2,4(1H,3H)-dione, 5, with phosphoryl chloride(POCl₃) can afford the trichloride pyrimidine of formula 6. Compound 6can be converted to the iodide of formula 7 using sodium iodide (NaI),tetrabutylammonium iodide (Bu₄NI), or an equivalent iodide reagent.Compound 7 can be coupled with aniline 3 in the presence of a suitablebase, such as diisopropylethylamine (¹Pr₂NEt), cesium carbonate(Cs₂CO₃), or sodium hydride (NaH), to give the dichloropyrimidine offormula 8.

The synthesis of compound 14 is outlined in Scheme 3. Compound 9 can betreated with ethyl 3-chloro-3-oxopropanoate and NaH in THF to provideamide 10. Lactam 11 can be prepared by the treatment of compounds 10with a strong base, such as NaH or Cs₂CO₃ in DMF, and followed by anacid, such as HCl, mediated decarboxylation. α-Substituted lactam 12 canbe obtained by treating compound 11 with a base, such as NaH or Cs₂CO₃in DMF or acetonitrile, and followed by the addition of halides R¹⁰Xand/or R¹¹X (X is halo such as Cl, Br, or I). Chloride 12 can beconverted to the compound 13 when treated with Zn(CN)₂/Pd(dppf)₂Cl₂ inDMF. The reduction of compound 13 with DIBAL-H can give thecorresponding amine, the acryloylation of which with acryloyl chloridein the presence of a base, such as iPr₂NEt, can afford amide 14.

Alkene 17 can be synthesized following the procedure shown in Scheme 4.Therefore, compound 9 is first treated with triphosgene in the presenceof a base such as pyridine, and then with amine R⁷NH₂ in the presence ofanother base (e.g. DIPEA) to afford urea 15. Upon treatment with aproper base (e.g. Cs₂CO₃), cyclization of 15 takes place to generatecyclic urea 16, which can then be converted to compound 17 usingstandard Suzuki conditions in the presence of4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane.

Alkene 17 can be prepared by an alternative procedure outlined in scheme5. The Suzuki coupling between compound 9 and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane can provide alkene 18,which can be converted to the corresponding amine 19 under standardBuchwald-Hartwig amination conditions using reagents such as, forexample, Pd(OAc)₂/Xantphos/Cs₂CO₃ or Pd₂(dba)₃/BINAP/NaOtBu, etc.Treatment of amine 19 with triphosgene in the presence of a base such asEt₃N or DIPEA can afford compound 17.

Compound 23 can be synthesized by the method described in Scheme 6. Theoxidative cleavage of the alkene 17 using OsO₄/NaIO₄ can providealdehyde 20. Compound 20 is then converted to the corresponding amine 21via reductive amination. The coupling reaction between amine 21 and acidchloride 22 can occur in the presence of a base, such as iPr₂NEt or Et₃Nto afford amide 23.

Methods of Use

Compounds of the invention can inhibit the activity of the FGFR4 enzyme.For example, the compounds of the invention can be used to inhibitactivity of an FGFR4 enzyme in a cell or in an individual or patient inneed of inhibition of the enzyme by administering an inhibiting amountof a compound of the invention to the cell, individual, or patient.

In some embodiments, the compounds of the invention are selective forthe enzyme FGFR4 over one or more of FGFR1, FGFR2, and/or FGFR3. In someembodiments, the compounds of the invention are selective for the enzymeFGFR4 over FGFR1, FGFR2, and FGFR3. In some embodiments, the compoundsof the invention are selective for the enzyme FGFR4 over VEGFR2. In someembodiments, the selectivity is 2-fold or more, 3-fold or more, 5-foldor more, 10-fold or more, 25-fold or more, 50-fold or more, or 100-foldor more.

As FGFR4 inhibitors, the compounds of the invention are useful in thetreatment of various diseases associated with abnormal expression oractivity of the FGFR4 enzyme or FGFR ligands. Compounds which inhibitFGFR will be useful in providing a means of preventing the growth orinducing apoptosis in tumors, particularly by inhibiting angiogenesis.It is therefore anticipated that the compounds will prove useful intreating or preventing proliferative disorders such as cancers. Inparticular tumours with activating mutants of receptor tyrosine kinasesor upregulation of receptor tyrosine kinases may be particularlysensitive to the inhibitors.

In certain embodiments, the FGFR4, or a mutant thereof, activity isinhibited irreversibly. In certain embodiments, FGFR4, or a mutantthereof, activity is inhibited irreversibly by covalently modifying Cys552 of FGFR4.

In certain embodiments, the invention provides a method for treating aFGFR4-mediated disorder in a patient in need thereof, comprising thestep of administering to said patient a compound according to theinvention, or a pharmaceutically acceptable composition thereof.

For example, the compounds of the invention are useful in the treatmentof cancer. Example cancers include bladder cancer, breast cancer,cervical cancer, colorectal cancer, cancer of the small intestine, coloncancer, rectal cancer, cacncer of the anus, endometrial cancer, gastriccancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx,nasopharynx, oropharynx, lips, and mouth), kidney cancer, liver cancer(e.g., hepatocellular carcinoma, cholangiocellular carcinoma), lungcancer (e.g., adenocarcinoma, small cell lung cancer and non-small celllung carcinomas, parvicellular and non-parvicellular carcinoma,bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma),ovarian cancer, prostate cancer, testicular cancer, uterine cancer,esophageal cancer, gall bladder cancer, pancreatic cancer (e.g. exocrinepancreatic carcinoma), stomach cancer, thyroid cancer, parathyroidcancer, skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma,Merkel cell skin cancer), and brain cancer (e.g., astrocytoma,medulloblastoma, ependymoma, neuro-ectodermal tumors, pineal tumors).

Further example cancers include hematopoietic malignancies such asleukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma,adult T cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acutemyelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma,myeloproliferative neoplasms (e.g., polycythemia vera, essentialthrombocythemia, and primary myelofibrosis), Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, chronic myelogenic lymphoma,acute lymphoblastic lymphoma, AIDS-related lymphomas, and Burkitt'slymphoma.

Other cancers treatable with the compounds of the invention includetumors of the eye, glioblastoma, melanoma, rhabdosarcoma, lymphosarcoma,and osteosarcoma.

The compounds of the invention can also be useful in the inhibition oftumor metastisis.

In some embodiments, the present invention provides a method fortreating hepatocellular carcinoma in a patient in need thereof,comprising the step of administering to said patient a compoundaccording to the invention, or a pharmaceutically acceptable compositionthereof.

In some embodiments, the present invention provides a method fortreating Rhabdomyosarcoma, esophageal cancer, breast cancer, or cancerof a head or neck, in a patient in need thereof, comprising the step ofadministering to said patient a compound according to the invention, ora pharmaceutically acceptable composition thereof.

In some embodiments, the present invention provides a method of treatingcancer, wherein the cancer is selected from hepatocellular cancer,breast cancer, bladder cancer, colorectal cancer, melanoma,mesothelioma, lung cancer, prostate cancer, pancreatic cancer,testicular cancer, thyroid cancer, squamous cell carcinoma,glioblastoma, neuroblastoma, uterine cancer, and rhabdosarcoma.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the FGFR4 enzyme with a compound of the inventionincludes the administration of a compound of the present invention to anindividual or patient, such as a human, having FGFR, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the FGFR4enzyme.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician.

As used herein the term “treating” or “treatment” refers to 1)preventing the disease; for example, preventing a disease, condition ordisorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease; 2) inhibiting the disease;for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology), or 3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology).

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withthe compounds of the present invention for treatment of FGFR-associateddiseases, disorders or conditions. The agents can be combined with thepresent compounds in a single dosage form, or the agents can beadministered simultaneously or sequentially as separate dosage forms.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present invention can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with the compounds of the presentinvention for the treatment of cancer include chemotherapeutic agents,targeted cancer therapies, immunotherapies or radiation therapy.Compounds of this invention may be effective in combination withanti-hormonal agents for treatment of breast cancer and other tumors.Suitable examples are anti-estrogen agents including but not limited totamoxifen and toremifene, aromatase inhibitors including but not limitedto letrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds of the present invention. These include anti-androgensincluding but not limited to flutamide, bicalutamide, and nilutamide,luteinizing hormone-releasing hormone (LHRH) analogs includingleuprolide, goserelin, triptorelin, and histrelin, LHRH antagonists(e.g. degarelix), androgen receptor blockers (e.g. enzalutamide) andagents that inhibit androgen production (e.g. abiraterone).

Compounds of the present invention may be combined with or in sequencewith other agents against membrane receptor kinases especially forpatients who have developed primary or acquired resistance to thetargeted therapy. These therapeutic agents include inhibitors orantibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 andagainst cancer-associated fusion protein kinases such as Bcr-Abl andEML4-Alk. Inhibitors against EGFR include gefitinib and erlotinib, andinhibitors against EGFR/Her2 include but are not limited to dacomitinib,afatinib, lapitinib and neratinib. Antibodies against the EGFR includebut are not limited to cetuximab, panitumumab and necitumumab.Inhibitors of c-Met may be used in combination with FGFR inhibitors.These include onartumzumab, tivantnib, and INC-280. Agents against Abl(or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib andthose against Alk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith FGFR inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compounds ofthe present invention include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with FGFR inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds of the present invention. In some embodiments,the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

Other suitable agents for use in combination with the compounds of thepresent invention include chemotherapy combinations such asplatinum-based doublets used in lung cancer and other solid tumors(cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatinplus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin orcarboplatin plus pemetrexed) or gemcitabine plus paclitaxel boundparticles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with the compounds of thepresent invention include: dacarbazine (DTIC), optionally, along withother chemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds according to the invention may also be combinedwith immunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB and PD-1, or antibodies to cytokines (IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions which refers toa combination of a compound of the invention, or its pharmaceuticallyacceptable salt, and at least one pharmaceutically acceptable carrier.These compositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), ocular, oral or parenteral. Methods forocular delivery can include topical administration (eye drops),subconjunctival, periocular or intravitreal injection or introduction byballoon catheter or ophthalmic inserts surgically placed in theconjunctival sac. Parenteral administration includes intravenous,intraarterial, subcutaneous, intraperitoneal, or intramuscular injectionor infusion; or intracranial, e.g., intrathecal or intraventricular,administration. Parenteral administration can be in the form of a singlebolus dose, or may be, for example, by a continuous perfusion pump.Pharmaceutical compositions and formulations for topical administrationmay include transdermal patches, ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of the inventionabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mash. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mash.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpre-formulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepre-formulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid pre-formulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, vaccines, antibodies,immune enhancers, immune suppressants, anti-inflammatory agents and thelike.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlabel, heavy metal or radio-labeled compounds of the invention thatwould be useful not only in imaging but also in assays, both in vitroand in vivo, for localizing and quantitating the FGFR enzyme in tissuesamples, including human, and for identifying FGFR enzyme ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes FGFR enzyme assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide that isincorporated in the instant radio-labeled compounds will depend on thespecific application of that radio-labeled compound. For example, for invitro FGFR enzyme labeling and competition assays, compounds thatincorporate 3H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S will generally be mostuseful. For radio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I,⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of3H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art.

A radio-labeled compound of the invention can be used in a screeningassay to identify/evaluate compounds. In general terms, a newlysynthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the FGFR4 enzyme. Accordingly, the abilityof a test compound to compete with the radio-labeled compound forbinding to the FGFR4 enzyme directly correlates to its binding affinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of FGFR-associated diseases ordisorders, obesity, diabetes and other diseases referred to herein whichinclude one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof one or more FGFR's as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. All the starting materials are commercially available or readilysynthezied according to procedures known in the art. Preparatory LC-MSpurifications of some of the compounds prepared were performed on Watersmass directed fractionation systems. The basic equipment setup,protocols, and control software for the operation of these systems havebeen described in detail in the literature. See e.g. “Two-Pump At ColumnDilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem.,4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methodsfor Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G.Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and“Preparative LC-MS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem.,6, 874-883 (2004). The compounds separated were typically subjected toanalytical liquid chromatography mass spectrometry (LCMS) for puritycheck under the following conditions: Instrument; Agilent 1100 series,LC/MSD, Column: Waters Sunfire™ C₁₈ 5 μm particle size, 2.1×5.0 mm,Buffers: mobile phase A: 0.025% TFA in water and mobile phase B:acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 2.0mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 1N-{[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]methyl}acrylamide

Step 1: 4,6-dichloronicotinaldehyde

To a stirred solution of 2,4-dichloro-5-carbethoxypyridine (10.0 g, 45.4mmol) in methylene chloride (100.0 mL), diisobutylaluminum hydride inmethylene chloride (50.0 mL, 1.0 M, 50.0 mmol) was added dropwise at−78° C. After 2 hours, the reaction was quenched with a saturatedsolution of Rochelle's salt. After stirring for 12 hours, the aqueoussolution was extracted with DCM (3×150 mL). The combined organic layerswere dried over Na₂SO₄ and concentrated in vacuo to afford the crudealdehyde (7.51 g, 42.9 mmol), which was used directly in the next stepwithout further purification. LC-MS calculated for C₆H₄Cl₂NO [M+H]⁺ m/z:176.0; found 176.0.

Step 2:N-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline

To a stirred solution of 2,6-difluoro-3,5-dimethoxyaniline (9.03 g, 47.7mmol), sodium triacetoxyborohydride (38.0 g, 180 mmol) in methylenechloride (60 mL)/trifluoroacetic acid (30 mL),4,6-dichloronicotinaldehyde (8.00 g, 45.5 mmol) was added in smallportions at room temperature. After 1 hour, the volatiles were removedin vacuo and saturated aqueous NaHCO₃ (200 mL) was added. The resultingmixture was extracted with DCM (3×150 mL). The organic layers werecombined, dried over Na₂SO₄, and concentrated. The residue was purifiedon silica gel (eluting with 0 to 0-40% EtOAc in hexanes) to afford thedesired product (15.0 g). LC-MS calculated for C14H₁₃Cl₂F₂N₂O₂ [M+H]⁺m/z: 349.0; found 349.1.

Step 3: ethyl3-[[(4,6-dichloropyridin-3-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate

To a stirred solution ofN-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(3.50 g, 10.0 mmol) in tetrahydrofuran (20 mL), NaH (60% w/w in mineraloil, 421 mg, 10.5 mmol) was added at room temperature. After 10 minutes,ethyl malonyl chloride (1.92 mL, 15.0 mmol) was added drop wise. Afteranother 1 hour, the reaction was quenched with saturated aqueous NH₄Cl,and extracted with DCM (3×100 mL). The organic layers were combined,dried over Na₂SO₄, and concentrated. The residue was purified on silicagel (eluting with 0 to 0-35% EtOAc in hexanes) to afford the desiredproduct (4.20 g, 9.1 mmol). LC-MS calculated for C₁₉H₁₉Cl₂F₂N₂O₅ [M+H]⁺m/z: 463.1; found 463.1.

Step 4: Ethyl6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-3-oxo-1,2,3,4-tetrahydro-2,7-naphthyridine-4-carboxylate

To a stirred solution of ethyl3-[[(4,6-dichloropyridin-3-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate(1.50 g, 3.24 mmol) in DMF (15. mL), NaH (60% w/w in mineral oil, 337mg, 8.42 mmol) was added at room temperature. The resulting mixture wasthen warmed up to 110° C. After 5 hours, the reaction was cooled to roomtemperature, saturated aqueous NH₄Cl (50 mL) was added to formprecipitate. After filtration, the solid was dried in vacuo to givecrude cyclized product (0.95 g, 2.23 mmol). LC-MS calculated forC₁₉H₁₈ClF₂N₂O₅ [M+H]⁺ m/z: 427.1; found 427.0.

Step 5:6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-1,2-dihydro-2,7-naphthyridin-3(4H)-one

To a stirred solution of ethyl6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-3-oxo-1,2,3,4-tetrahydro-2,7-naphthyridine-4-carboxylate(0.95 g, 2.23 mmol) in 1,4-dioxane (5 mL) hydrogen chloride (4.0 M indioxane, 2 mL, 8 mmol) was added at room temperature. The resultingmixture was warmed up to 100° C. After 4 hours, the reaction was cooledto ambient temperature, quenched with saturated aqueous NaHCO₃, andextracted with DCM (3×100 mL). The organic layers were combined, driedover Na₂SO₄, and concentrated. The residue was purified on silica gel(eluting with 0 to 0-30% EtOAc in DCM) to afford the desired product(0.75 g, 2.12 mmol). LC-MS calculated for C₁₆H₁₄ClF₂N₂O₃ [M+H]⁺ m/z:355.1; found 355.1.

Step 6:6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one

To a stirred solution of6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-1,4-dihydro-2,7-naphthyridin-3(2H)-one(1.50 g, 4.23 mmol) in DMF (10 mL), cesium carbonate (3.03 g, 9.30 mmol)and 1-bromo-2-chloro-ethane (701 μL, 8.46 mmol) were added sequentiallyat room temperature. After 5 hours, the reaction was quenched withsaturated aqueous NH₄Cl, and extracted with DCM (3×75 mL). The organiclayers were combined, dried over Na₂SO₄, and concentrated. The residuewas purified on silica gel (eluting with 0 to 0-50% EtOAc in hexanes) toafford the desired product (1.20 g, 3.15 mmol). LC-MS calculated forC₁₈H₁₆ClF₂N₂O₃ [M+H]⁺ m/z: 381.1; found 381.1.

Step 7:2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-carbonitrile

A reaction mixture of6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one(0.40 g, 1.0 mmol), zinc cyanide (0.12 g, 1.0 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (86 mg, 0.10 mmol) in N,N-dimethylformamide(6.9 mL) was stirred at 130° C. under an atmosphere of N₂ for 6 hours.The reaction was quenched with saturated aqueous NaHCO₃, and extractedwith ethyl acetate (3×20 mL). The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was purified on silica gel (eluting with 0 to0-20% EtOAc in DCM) to afford the desired product (0.28 g). LC-MScalculated for C₁₉H₁₆F₂N₃O₃ [M+H]⁺ m/z: 372.1; found 372.1.

Step 8:6′-(aminomethyl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one

To a stirred solution of2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-carbonitrile(99.9 mg, 0.269 mmol) in THF (5 mL), diisobutylaluminum hydride (1.0 Min toluene, 0.54 mL, 0.54 mmol) was added at −78° C. After 2 hours, thereaction mixture was quenched with saturated aqueous NH₄Cl, andextracted with ethyl acetate (3×20 mL). The combined organic layers werewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product (15 mg) as its TFAsalt. LC-MS calculated for C₁₉H₂₀F₂N₃O₃ [M+H]⁺ m/z: 376.2; found 376.1.

Step 9:N-{[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]methyl}acrylamide

To a stirred solution of6′-(aminomethyl)-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one(25.5 mg, 0.068 mmol) in methylene chloride (4.0 mL),N,N-diisopropylethylamine (46 μL, 0.27 mmol) and 2-propenoyl chloride(5.8 μL, 0.072 mmol) were added sequentially at room temperature. After3 minutes, the reaction was quenched with saturated aqueous NH₄Cl,extracted with methylene chloride. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated to dryness under reducedpressure. The crude product was purified on prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product (15 mg) as its TFAsalt. LCMS calculated for C₂₂H₂₂F₂N₃O₄ [M+H]⁺ m/z: 430.2; Found: 430.1.¹H NMR (500 MHz, DMSO-d₆): δ 8.63 (t, J=5.6 Hz, 1H), 8.40 (s, 1H), 7.07(t, J=8.2 Hz, 1H), 6.97 (s, 1H), 6.31 (dd, J=17.1, 10.2 Hz, 1H), 6.11(dd, J=17.1, 2.1 Hz, 1H), 5.62 (dd, J=10.2,2.1 Hz, 1H), 4.95 (s, 2H),4.43 (d, J=5.8 Hz, 2H), 3.89 (s, 6H), 1.76 (q, J=3.9 Hz, 2H), 1.46 (q,J=4.0 Hz, 2H).

Example 2N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

Step 1:7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To a solution of triphosgene (344 mg, 1.16 mmol) in CH₂Cl₂ (12 mL, 190mmol) at 0° C. was first added pyridine (0.250 mL, 3.09 mmol). Thereaction mixture was then stirred at 0° C. for 10 minutes, followed bythe addition of a solution ofN-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(prepared as in Example 1, Step 2, 900 mg, 2.58 mmol) in CH₂Cl₂ (8.0mL). The reaction mixture was stirred at 0° C. for 1 hour, after whichtime ethylamine in THF (2.0 M, 6.4 mL, 13 mmol) was added to thereaction mixture, followed by the addition of N,N-diisopropylethylamine(920 μL, 5.3 mmol). The resulting mixture was then warmed to roomtemperature, stirred overnight, quenched with saturated NaHCO₃ (aqueoussolution), and extracted with EtOAc (3×20 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated to give the crudeintermediate1-((4,6-dichloropyridin-3-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea.The crude intermediate was first dissolved in DMF (20 mL), followed bythe addition of Cs₂CO₃ (1.70 g, 5.2 mmol). The reaction mixture was thenstirred at 95° C. for 5 hours until completion, cooled to roomtemperature, quenched with water, and extracted with EtOAc (3×20 mL).The combined organic layers were dried over Na₂SO₄, and concentrated.The resulting material was purified via column chromatography (25% to55%) EtOAc in hexanes) to give the product as a slightly yellow solid.LC-MS calculated for C₁₇H₁₇ClF₂N₃O₃ [M+H]⁺ m/z: 384.1; found 384.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-vinyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

A mixture of7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(460 mg, 1.20 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(240 μL, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 g,0.07 mmol) and potassium carbonate (0.66 g, 4.8 mmol) in 1,4-dioxane (12mL) and water (4.3 mL) was stirred at 120° C. overnight. The reactionwas quenched with saturated aqueous NaHCO₃, and extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified on silica gel (eluting with 0 to 0-40% EtOAc inhexanes) to afford the desired product. LC-MS calculated forC₁₉H₂₀F₂N₃O₃ [M+H]⁺ m/z: 376.1; found 376.1.

Step 3:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carbaldehyde

To a solution of3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-vinyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.32 g, 0.85 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was addedosmium tetraoxide (0.81 mL, 4% w/w, 0.13 mmol) at room temperature. Thereaction mixture was stirred for 5 minutes then sodium periodate (0.547g, 2.56 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 hour, then diluted with water and extracted withEtOAc. The combined extracts were washed with water and brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was used in the next step without further purification.

Step 4:(E)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carbaldehydeoxime

Hydroxylamine hydrochloride (0.21 g, 3.0 mmol) was added to a slurry ofcrude3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carbaldehyde(0.31 g, 0.80 mmol) and potassium carbonate (0.12 g, 0.85 mmol) inmethanol (6 mL) at room temperature. The resulting mixture was stirredat 70° C. for 1 hour. The volatiles were removed and the residue wasdiluted with ethyl acetate (20 mL). The organic layer was washed withsaturated aqueous NaHCO₃ solution, brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was used directlyin the next step. LC-MS calculated for C₁₈H₁₉F₂N₄O₄ [M+H]⁺ m/z: 393.1;found 393.1.

Step 5:7-(aminomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

Zinc (440 mg, 6.8 mmol) was added in several portions to a solution ofcrude(E)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine-7-carbaldehyde oxime (0.30 g, 0.76 mmol) in aceticacid (3 mL) at room temperature. The resulting reaction mixture wasstirred at room temperature for 1 hour. The reaction was quenched withsaturated aqueous NaHCO₃, and extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure. Hydrogen chloride(0.54 mL, 4.0 M in 1,4-dioxane, 2.2 mmol) was added to the residue. Themixture was concentrated in vacuo to afford the crude product (0.30 g)as its HCl salt. LC-MS calculated for C₁₈H₂₁F₂N₄O₃ [M+H]⁺ m/z: 379.2;found 379.1.

Step 6:N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

To a stirred solution of crude7-(aminomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one(0.28, 0.74 mmol) and triethylamine (350 μL, 2.5 mmol) in acetonitrile(5 mL), 2-propenoyl chloride (70 μL, 0.86 mmol) was added at roomtemperature. After 30 minutes, the reaction mixture was diluted withMeOH and was purified by RP-HPLC (pH=2) to afford the desired product asits TFA salt. LC-MS calculated for C₂₁H₂₃F₂N₄O₄ [M+H]⁺ m/z: 433.2; found433.1. ¹H NMR (500 MHz, DMSO-d₆): δ 8.87 (s, 1H), 8.38 (s, 1H), 7.33 (s,1H), 7.08 (t, J=8.2 Hz, 1H), 6.32 (dd, J=17.1, 10.2 Hz, 1H), 6.15 (dd,J=17.1, 2.0 Hz, 1H), 5.68 (dd, J=10.2, 2.0 Hz, 1H), 4.84 (s, 2H), 4.57(d, J=5.6 Hz, 2H), 3.92 (q, J=5.0 Hz, 2H), 3.89 (s, 6H), 1.18 (t, J=7.0Hz, 3H).

Example 3N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

Step 1:N-((4-chloro-6-vinylpyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline

A mixture ofN-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(prepared as in Example 1, Step 2, 2.00 g, 5.73 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.98 mL, 5.8 mmol),tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.3 mmol) and potassiumcarbonate (3.2 g, 23 mmol) in 1,4-dioxane (10 mL) and water (2.0 mL) wasstirred at 120° C. overnight. The reaction mixture was quenched withsaturated aqueous NaHCO₃, and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified on silica gel (eluting with 0 to 0-25% EtOAc in hexanes) toafford the desired product (1.3 g). LC-MS calculated for C₁₆H₁₆ClF₂N₂O₂[M+H]⁺ m/z: 341.1; found 341.1.

Step 2:3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-3-yl)-7-vinyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

To a stirred solution ofN-[(4-chloro-6-vinylpyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(100.0 mg, 0.2935 mmol), palladium acetate (6.6 mg, 0.029 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (18 mg, 0.029 mmol),and cesium carbonate (290 mg, 0.89 mmol) in 1,4-dioxane (6 mL, 80 mmol)was added 3-pyridinamine (39 mg, 0.41 mmol). The resulting mixture wasstirred at 130° C. overnight under the atmosphere of N₂. After coolingto room temperature, the reaction mixture was diluted with ethylacetate, filtered and concentrated under reduced pressure. The crudeN-(5-(((2,6-difluoro-3,5-dimethoxyphenyl)amino)methyl)-2-vinylpyridin-4-yl)pyridin-3-aminewas used without further purification. LC-MS calculated for C₂₁H₂₁F₂N₄O₂[M+H]⁺ m/z: 399.2; found 399.2.

Triphosgene (87 mg, 0.29 mmol) was added to a solution of the crudeN-(5-(((2,6-difluoro-3,5-dimethoxyphenyl)amino)methyl)-2-vinylpyridin-4-yl)pyridin-3-amineand N,N-diisopropylethylamine (310 μL, 1.8 mmol) in tetrahydrofuran (5mL) at 0° C. After 15 minutes, the reaction was quenched with saturatedaqeuous NaHCO₃, diluted with EtOAc. The organic layer was separated andwashed with water, dried over Na₂SO₄, filtered and concentrated in vacuoto afford the desired product, which was used directly in the next stepwithout further purification. LC-MS calculated for C₂₂H₁₉F₂N₄O₃ [M+H]⁺m/z: 425.2; found 425.2.

Step 3:N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, Steps 3 to 6, with3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(pyridin-3-yl)-7-vinyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-onereplacing3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-vinyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-onein step 3. LCMS calculated for C₂₄H₂₂F₂N₅O₄ [M+H]⁺ m/z: 482.2; Found:482.2.

Example 4N-((6′-(2,6-difluoro-3,5-dimethoxyphenyl)-7′-oxo-6′,7′-dihydro-5′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-2′-yl)methyl)acrylamide

Step 1: 2,4-dichloro-5-(chloromethyl)pyrimidine

To a stirred solution of 5-(hydroxymethyl)uracil (5.0 g, 35 mmol) inphosphoryl chloride (25 mL, 270 mmol) and toluene (6.0 mL),N,N-diisopropylethylamine (26 mL, 150 mmol) was added dropwise at roomtemperature. The resulting solution was heated at 110° C. overnight.After being cooled to room temperature, the reaction mixture wasconcentrated under reduced pressure, diluted with 1N HCl (100 mL) andwater (200 mL), and was extracted with DCM. The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated. The residue waspurified on silica gel (eluting with 0-40% EtOAc in DCM) to give 6.4 gof the desired product. LCMS calculated for C₅H₄Cl₃N₂ [M+H]⁺ m/z: 196.9;Found: 197.0.

Step 2: 2,4-dichloro-5-(iodomethyl)pyrimidine

To a stirred solution of 2,4-dichloro-5-(chloromethyl)pyrimidine (1.50g, 7.60 mmol) in acetone (10 mL), sodium iodide (1.20 g, 7.98 mmol) wasadded at room temperature. After stirring for 5 hours, the reactionmixture was filtered and the solid was washed with acetone. The filtrateand washed solution were combined and concentrated. The residue waspurified on silica gel (eluting with 0-40% EtOAc in hexanes) to give 1.5g of the desired product. LCMS calculated for C₅H₄Cl₂IN₂ [M+H]⁺ m/z:288.9; Found: 288.8.

Step 3:N-[(2,4-dichloropyrimidin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline

A mixture of 2,4-dichloro-5-(iodomethyl)pyrimidine (1.50 g, 5.19 mmol),2,6-difluoro-3,5-dimethoxyaniline (1.08 g, 5.71 mmol) inN,N-diisopropylethylamine (4 mL) was stirred at 80° C. for 2 hours.After being cooled to room temperature, the reaction mixture wasconcentrated under reduced pressure. The residue was purified on silicagel (eluting with 0-40% EtOAc in DCM) to give 1.70 g of the desiredproduct. LCMS calculated for C₁₃H₁₂Cl₂F₂N₃O₂ [M+H]⁺ m/z: 350.0; Found:350.0.

Step 4: ethyl3-(((2,4-dichloropyrimidin-5-yl)methyl)(2,6-difluoro-3,5-dimethoxyphenyl)amino)-3-oxopropanoate

The title compound was prepared using procedures analogous to thosedescribed for Example 1, Step 3, withN-[(2,4-dichloropyrimidin-5-yl)methyl]-2,6-difluoro-3,5-dimethoxyanilinereplacingN-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline.LCMS calculated C₁₈H₁₈Cl₂F₂N₃O₅ [M+H]⁺ m/z: 464.1; Found: 464.0.

Step 5: ethyl2-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylate

A mixture of ethyl3-[[(2,4-dichloropyrimidin-5-yl)methyl](2,6-difluoro-3,5-dimethoxyphenyl)amino]-3-oxopropanoate(1.2 g, 2.6 mmol) and2-(tert-butylimino)-N,N-diethyl-1,3-dimethyl-1,3,2λ(5)-diazaphosphinan-2-amine(1.5 mL, 5.17 mmol) in methylene chloride (6 mL) was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure and the residue was purified on silica gel (elutingwith 0-40% EtOAc in DCM) to give 0.88 g of the desired product. LCMScalculated for C₁₈H₁₇ClF₂N₃O₅ [M+H]⁺ m/z: 428.1; Found: 428.0.

Step 6:2-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one

The title compound was prepared using procedures analogous to thosedescribed for Example 1, Step 5, with ethyl2-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylatereplacing6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-3-oxo-1,2,3,4-tetrahydro-2,7-naphthyridine-4-carboxylate.LCMS calculated Cl₅H₁₃ClF₂N₃O₃ [M+H]⁺ m/z: 356.1; Found: 356.1.

Step 7:2′-chloro-6′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidin]-7′-one

The title compound was prepared using procedures analogous to thosedescribed for Example 1, Step 6, with2-chloro-6-(2,6-difluoro-3,5-dimethoxyphenyl)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-onereplacing6-chloro-2-(2,6-difluoro-3,5-dimethoxyphenyl)-1,4-dihydro-2,7-naphthyridin-3(2H)-one.LCMS calculated C₁₇H₁₅ClF₂N₃O₃ [M+H]⁺ m/z: 382.1; Found: 382.0.

Step 8:N-((6′-(2,6-difluoro-3,5-dimethoxyphenyl)-7′-oxo-6′,7′-dihydro-5′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-2′-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, Steps 2 to 6, with2′-chloro-6′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidin]-7′-onereplacing7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-onein step 2. LCMS calculated for C₂₁H₂₁F₂N₄O₄ [M+H]⁺ m/z: 431.2; Found:431.1.

Example 5N-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide

Step 1:6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopentane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

The title compound was prepared using procedures analogous to thosedescribed for Example 1, Step 6, with 1,4-dibromobutane replacing1-bromo-2-chloro-ethane. LCMS calculated for C₂₀H₂₀ClF₂N₂O₃ [M+H]⁺ m/z:409.1; Found: 409.1.

Step 2:N-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, Steps 2 to 6, with6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-1′H-spiro[cyclopentane-1,4′-[2,7]naphthyridin]-3′(2′H)-onereplacing7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-onein step 2. LCMS calculated for C₂₄H₂₆F₂N₃O₄ [M+H]⁺ m/z: 458.2; Found:458.2. ¹H NMR (600 MHz, DMSO) δ 8.74 (t, J=5.7 Hz, 1H), 8.50 (s, 1H),7.36 (s, 1H), 7.07 (t, J=8.1 Hz, 1H), 6.34 (dd, J=17.1, 10.3 Hz, 1H),6.15 (dd, J=17.1, 2.0 Hz, 1H), 5.65 (dd, J=10.3, 2.0 Hz, 1H), 4.87 (s,2H), 4.51 (d, J=5.9 Hz, 2H), 3.90 (s, 6H), 2.38 (dt, J=14.4, 7.4 Hz,2H), 1.98 (dt, J=12.3, 6.4 Hz, 2H), 1.87-1.73 (m, 4H).

Example 6N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-phenyl-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 3, with aniline replacing 3-pyridinamine in Step2. LCMS calculated for C₂₅H₂₃F₂N₄O₄ [M+H]⁺ m/z: 481.2; Found: 481.2.

Example 7N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 3, with 1-methyl-1H-pyrazol-3-amine replacing3-pyridinamine in Step 2. LCMS calculated for C₂₃H₂₃F₂N₆O₄ [M+H]⁺ m/z:485.2; Found: 485.2.

Example 8(S)—N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 3, with (S)-tetrahydrofuran-3-amine replacing3-pyridinamine in Step 2. LCMS calculated for C₂₃H₂₅F₂N₄O₅ [M+H]⁺ m/z:475.2; Found: 475.1.

Example 9N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3,3-difluorocyclobutyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 3, with 3,3-difluorocyclobutanamine replacing3-pyridinamine in Step 2. LCMS calculated for C₂₃H₂₃F₄N₄O₄ [M+H]⁺ m/z:495.2; Found: 495.2.

Example 10N-((1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with cyclopropanamine replacing ethylamine inStep 1. LCMS calculated for C₂₂H₂₃F₂N₄O₄ [M+H]⁺ m/z: 445.2; Found:445.2.

Example 11N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with 2-methoxyethanamine replacing ethylaminein Step 1. LCMS calculated for C₂₂H₂₅F₂N₄O₅ [M+H]⁺ m/z: 463.2; Found:463.2. ¹H NMR (500 MHz, DMSO-d₆): δ 8.83 (t, J=5.7 Hz, 1H), 8.35 (s,1H), 7.36 (s, 1H), 7.07 (t, J=8.2 Hz, 1H), 6.33 (dd, J=17.1, 10.2 Hz,1H), 6.15 (dd, J=17.1, 2.0 Hz, 1H), 5.68 (dd, J=10.2, 2.0 Hz, 1H), 4.82(s, 2H), 4.52 (d, J=5.8 Hz, 2H), 4.06 (t, J=5.6 Hz, 2H), 3.89 (s, 6H),3.55 (t, J=5.6 Hz, 2H), 3.22 (s, 3H).

Example 12N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-propyl-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with propan-1-amine replacing ethylamine inStep 1. LCMS calculated for C₂₂H₂₅F₂N₄O₄ [M+H]⁺ m/z: 447.2; Found:447.2.

Example 13N-((1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with cyclopropylmethanamine replacingethylamine in Step 1. LCMS calculated for C₂₃H₂₅F₂N₄O₄ [M+H]⁺ m/z:459.2; Found: 459.1.

Example 14N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with 2,2-difluoroethanamine replacingethylamine in Step 1. LCMS calculated for C₂₁H₂₁F₄N₄O₄ [M+H]⁺ m/z:469.2; Found: 469.1.

Example 15N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with propan-2-amine replacing ethylamine inStep 1. LCMS calculated for C₂₂H₂₅F₂N₄O₄ [M+H]⁺ m/z: 447.2; Found: 447.2

Example 16N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with (3-fluorophenyl)methanamine replacingethylamine in Step 1. LCMS calculated for C₂₆H₂₄F₃N₄O₄ [M+H]⁺ m/z:513.2; Found: 513.2

Example 17N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with pyridin-3-ylmethanamine replacingethylamine in Step 1. LCMS calculated for C₂₅H₂₄F₂N₅O₄ [M+H]⁺ m/z:496.2; Found: 496.2

Example 18N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with pyridin-3-ylmethanamine replacingethylamine in Step 1. LCMS calculated for C₂₄H₂₅F₂N₆O₄ [M+H]⁺ m/z:499.2; Found: 499.2

Example 19(R)—N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with (R)-(tetrahydrofuran-3-yl)methanaminereplacing ethylamine in Step 1. LCMS calculated for C₂₄H₂₇F₂N₄O₅ [M+H]⁺m/z: 489.2; Found: 489.2

Example 20N-((1-(cyanomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with 2-aminoacetonitrile replacing ethylaminein Step 1. LCMS calculated for C₂₁H₂₀F₂N₅O₄ [M+H]⁺ m/z: 444.2; Found:444.2

Example 21N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with 2,2,2-trifluoroethanamine replacingethylamine in Step 1. LCMS calculated for C₂₁H₂₀F₅N₄O₄ [M+H]⁺ m/z:487.1; Found: 487.1

Example 22N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with methylamine replacing ethylamine inStep 1. LCMS calculated for C₂₀H₂₁F₂N₄O₄ [M+H]⁺ m/z: 419.2; Found: 419.1

Example 23N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with tetrahydro-2H-pyran-4-amine replacingethylamine in Step 1. LCMS calculated for C₂₄H₂₇F₂N₄O₅ [M+H]⁺ m/z:489.2; Found: 489.2

Example 24N-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 1, with methyl iodide replacing1-bromo-2-chloro-ethane in Step 6. LCMS calculated for C₂₂H₂₄F₂N₃O₄[M+H]⁺ m/z: 432.2; Found: 432.2

Example 25N-((1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with cyclobutylamine replacing ethylamine inStep 1. LCMS calculated for C₂₃H₂₅F₂N₄O₄ [M+H]⁺ m/z: 459.2; Found:459.1. ¹H NMR (500 MHz, dmso) δ 8.82 (t, J=5.8 Hz, 1H), 8.38 (s, 1H),7.05 (t, J=8.1 Hz, 1H), 6.98 (s, 1H), 6.33 (dd, J=17.1, 10.2 Hz, 1H),6.14 (dd, J=17.1, 2.0 Hz, 1H), 5.67 (dd, J=10.2, 2.0 Hz, 1H), 4.73 (s,2H), 4.50 (d, J=5.9 Hz, 2H), 4.45-4.38 (m, 1H), 3.88 (s, 6H), 2.49 (m,2H), 2.18-2.05 (m, 2H), 1.77-1.69 (m, 2H).

Example 26N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-4-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 3, with 4-aminopyridine replacing 3-pyridinaminein Step 2. LCMS calculated for C₂₄H₂₂F₂N₅O₄ [M+H]⁺ m/z: 482.2; Found:482.1

Example 27N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with 2-fluoroethylamine hydrochloride replacingethylamine in Step 1. LCMS calculated for C₂₁H₂₂F₃N₄O₄ [M+H]⁺ m/z:451.2; Found: 451.1

Example 28N-((1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 3, with cyclopentylamine replacing 3-pyridinaminein Step 2. LCMS calculated for C₂₄H₂₇F₂N₄O₄ [M+H]⁺ m/z: 473.2; Found:473.1

Example 29N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with 2-methylpropan-1-amine replacingethylamine in Step 1. LCMS calculated for C₂₃H₂₇F₂N₄O₄ [M+H]⁺ m/z:461.2; Found: 461.2

Example 30N-((1-(cyclobutylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with cyclobutylmethanamine replacing ethylaminein Step 1. LCMS calculated for C₂₄H₂₇F₂N₄O₄ [M+H]⁺ m/z: 473.2; Found:473.2

Example 31(S)—N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with (S)-(tetrahydrofuran-3-yl)methanaminereplacing ethylamine in Step 1. LCMS calculated for C₂₄H₂₇F₂N₄O₅ [M+H]⁺m/z: 489.2; Found: 489.2

Example 32N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

Step 1:4-chloro-5-((2,6-difluoro-3,5-dimethoxyphenylamino)methyl)picolinonitrile

A stirred mixture ofN-[(4,6-dichloropyridin-3-yl)methyl]-2,6-difluoro-3,5-dimethoxyaniline(prepared as in Example 1, Step 2, 3.50 g, 10.0 mmol), zinc cyanide(0.79 g, 6.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.92 g,1.0 mmol) and[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed withdichloromethane (1:1) (0.82 g, 1.0 mmol) in N,N-dimethylformamide (50mL) was heated at 125-130° C. under an atmosphere of N₂ for 1.5 hours.The reaction mixture was then cooled to room temperature, quenched withsaturated aqueous NaHCO₃, and extracted with ethyl acetate (3×100 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified on silica gel (eluting with 0-25% EtOAc in hexanes) to give2.57 g of the desired product. LCMS calculated for C₁₅H₁₃ClF₂N₃O₂ [M+H]⁺m/z: 340.1; Found: 340.0

Step 2: tert-butyl4-{[7-cyano-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl]methyl}piperidine-1-carboxylate

A stirred mixture of4-chloro-5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}pyridine-2-carbonitrile(200 mg, 0.6 mmol), tert-butyl 4-(aminomethyl)piperidinecarboxylate (170μL, 0.82 mmol), palladium acetate (13 mg, 0.059 mmol),(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, 0.059 mmol),and cesium carbonate (580 mg, 1.8 mmol) in 1,4-dioxane (10 mL) washeated at 110° C. under an atmosphere of N₂ for 5 hours. The reactionmixture was cooled to room temperature, diluted with ethyl acetate,filtered and the filtrate was concentrated under reduced pressure. Theresidue was used directly in the next step without further purification.

To a stirred solution of the above residue in tetrahydrofuran (8 mL),N,N-diisopropylethylamine (620 μL, 3.5 mmol) and triphosgene (170 mg,0.59 mmol) was added sequentially at room temperature. After 30 minutes,NaOH (2 N in water, 2 mL) was added. The resulting mixture was stirredat 30° C. for 1 hour. The reaction was quenched with saturated aqueousNaHCO₃, and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified on silicagel (eluting with 0-45% EtOAc in hexanes) to give 0.20 g of the desiredproduct. LCMS calculated for C₂₇H₃₁F₂N₅NaO₅ [M+Na]⁺ m/z: 566.2; Found:566.2

Step 3: tert-butyl4-((7-(aminomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate

To a solution of tert-butyl4-{[7-cyano-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl]methyl}piperidine-1-carboxylate(200 mg, 0.4 mmol) in methanol (5.0 mL), HCl (1.0 M in water, 680 μL,0.68 mmol) and Pd/C (10% w/w, 20 mg) were added sequentially at roomtemperature. The resulting mixture was stirred at room temperature underan atmosphere of H₂ for 2 hours. The reaction mixture was filtered, andthe filtrate was concentrated under reduced pressure to afford the crudeproduct as its HCl salt. LCMS calculated for C₂₇H₃₆F₂N₅O₅ [M+H]⁺ m/z:548.3; Found: 548.3.

Step 4: tert-butyl4-((7-(acrylamidomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-((7-(aminomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-djpyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate(186 mg, 0.34 mmol) in acetonitrile (2 mL), triethylamine (160 μL, 1.1mmol) and 2-propenoyl chloride (27 μL, 0.34 mmol) were addedsequentially at room temperature. After 30 minutes, the reaction wasquenched with saturated aqueous NaHCO₃, and extracted with ethyl acetate(3×20 mL). The combined organic layers were washed with brine, driedover MgSO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified on silica gel (eluting with 0-100%EtOAc in DCM) to give 0.09 g the desired product. LCMS calculated forC₃₀H₃₈F₂N₅O₆ [M+H]⁺ m/z: 602.3; Found: 602.2.

Step 5:N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

To a stirred solution of tert-butyl4-((7-(acrylamidomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-djpyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate (90 mg, 0.15mmol) in DCM (1 mL), TFA (1 mL) was added at room temperature. After 1hour, the volatiles were removed under reduced pressure to give desiredproduct as its TFA salt. LCMS calculated for C₂₅H₃₀F₂N₅O₄ [M+H]⁺ m/z:502.2; Found: 502.2.

Step 6:N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

To a stirred solution ofN-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl]methyl}acrylamide2,2,2-trifluoroacetate (15 mg, 0.030 mmol) in tetrahydrofuran (1 mL),formaldehyde (10.0 M in water, 6.2 μL, 0.062 mmol) andN,N-diisopropylethylamine (14 μL, 0.082 mmol) were added sequentially atroom temperature. After 5 minutes, sodium triacetoxyborohydride (13 mg,0.062 mmol) was added. After another 2 hours, the reaction mixture wasdiluted with MeOH and purified by RP-HPLC (pH=10,acetonitrile/water+NH₄OH) to afford the desired product. LCMS calculatedfor C₂₆H₃₂F₂N₅O₄ [M+H]⁺ m/z: 516.2; Found: 516.2.

Example 33 methyl4-((7-(acrylamidomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate

To a stirred solution ofN-{[3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl]methyl}acrylamide2,2,2-trifluoroacetate (prepared as in Example 32, Step 5, 15 mg, 0.030mmol) in tetrahydrofuran (1.0 mL), N,N-diisopropylethylamine (14 μL,0.082 mmol) and methyl chloroformate (2.4 μL, 0.031 mmol) were addedsequentially at room temperature. After 30 minutes, the reaction mixturediluted with MeOH and purified by RP-HPLC (pH=10,acetonitrile/water+NH₄OH) to afford the desired product. LCMS calculatedfor C₂₇H₃₂F₂N₅O₆ [M+H]⁺ m/z: 560.2; Found: 560.3.

Example 344-((7-(acrylamidomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)-N-isopropylpiperidine-1-carboxamide

The title compound was prepared using procedures analogous to thosedescribed for Example 33, with 2-isocyanatopropane replacing methylchloroformate. LCMS calculated for C₂₉H₃₇F₂N₆O₅ [M+H]⁺ m/z: 587.3;Found: 587.2

Example 35N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 33, with methanesulfonyl chloride replacing methylchloroformate. LCMS calculated for C₂₆H₃₂F₂N₅O₆S [M+H]⁺ m/z: 580.2;Found: 580.1

Example 36N-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

Step 1: N-(3,5-dimethoxyphenyl)acetamide

To a stirred solution of 3,5-dimethoxyaniline (15.0 g, 97.9 mmol) intoluene (200 mL) was added acetic anhydride (10.2 mL, 108 mmol)dropwise. After 3 hours, the reaction mixture was diluted with 100 mLhexanes, filter and the solid was washed with toluene/hexane(2:1, 30mL), then hexanes. The solid was dried under reduced pressure to givethe desired compound (18.9 g). LCMS calculated for C₁₀H₁₄NO₃ [M+H]⁺ m/z:196.1; Found: 196.2.

Step 2: N-(2,6-dichloro-3,5-dimethoxyphenyl)acetamide

To a stirred suspension of N-(3,5-dimethoxyphenyl)acetamide (16.0 g,82.0 mmol) in acetonitrile (200 mL), sulfuryl chloride (13.0 mL, 160mmol) was added dropwise over 5 minutes at 0° C. After 30 minutes, thereaction was quenched with saturated aqueous NaHCO₃ (125 mL), filteredand the solid was washed with water and hexanes to afford the desiredproduct, (8.5 g). The filtrate was diluted with 100 mL of saturatedaqueous NaHCO₃ then extracted with EtOAc. The organic layers werecombined, washed with water, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified on silica gel (eluting with 0-40% EtOAc in hexanes) to affordanother 10.0 g of the desired product. LCMS calculated for C₁₀H₁₂Cl₂NO₃[M+H]⁺ m/z: 264.0; Found: 263.9.

Step 3: 2,6-dichloro-3,5-dimethoxyaniline

N-(2,6-dichloro-3,5-dimethoxyphenyl)acetamide (8.5 g, 32 mmol) wasdissolved in ethanol (160 mL) then a solution of potassium hydroxide(9.0 g, 160 mmol) in water (80 mL) was added. The mixture was heated toreflux and stirred for 48 hours. After the reaction was cooled to roomtemperature, the white precipitate was collected via filtration andwashed with cold water then dried to get the desired product (6.0 g).LCMS calculated for C₈H₁₀Cl₂NO₂ [M+H]⁺ m/z: 222.0; Found: 221.9.

Step 4:2,6-dichloro-N-((4,6-dichloropyridin-3-yl)methyl)-3,5-dimethoxyaniline

The title compound was prepared using procedures analogous to thosedescribed for Example 1, Step 2 with 2,6-dichloro-3,5-dimethoxyanilinereplacing 2,6-difluoro-3,5-dimethoxyaniline. LCMS calculated forC₁₄H₁₃Cl₄N₂O₂ [M+H]⁺ m/z: 381.0; Found: 381.0

Step 5:N-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, with2,6-dichloro-N-((4,6-dichloropyridin-3-yl)methyl)-3,5-dimethoxyaniline(Step 4) replacing2,6-difluoro-N-((4,6-dichloropyridin-3-yl)methyl)-3,5-dimethoxyanilinein Step 1. LCMS calculated for C₂₁H₂₃Cl₂N₄O₄ [M+H]⁺ m/z: 465.1; Found:465.1.

Example 37N-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′-methyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide

Step 1: (4,6-dichloro-5-methylpyridin-3-yl)methanol

To a stirred solution of ethyl 4,6-dichloro-5-methylnicotinate (6.70 g,28.6 mmol) in methylene chloride (100 mL), diisobutylaluminum hydride(1.0 M in toluene, 60. mL, 60. mmol) was added dropwise at −78° C. After1 hour, the reaction mixture was quenched with saturated aqueouspotassium sodium tartrate (7 mL) then stirred at room temperatureovernight. The organic layer was separated and the aqueous layer wasextracted with DCM. The combined organic layers were dried over MgSO₄,filtered and concentrated under reduced pressure to afford the crudeproduct (5.46 g). LCMS calculated for C₇H₈Cl₂NO [M+H]⁺ m/z: 192.0;Found: 192.0

Step 2:N-((4,6-dichloro-5-methylpyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline

To a stirred solution of (4,6-dichloro-5-methylpyridin-3-yl)methanol(5.46 g, 28.4 mmol) in methylene chloride (100 mL),N,N-diisopropylethylamine (9.90 mL, 56.9 mmol) and methanesulfonylchloride (2.9 mL, 37 mmol) were added sequentially at 0° C. Afteranother 2 hours, the reaction mixture was quenched with saturatedaqueous NaHCO₃, and extracted with DCM (3×100 mL). The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was used in the nextstep without further purification.

2,6-difluoro-3,5-dimethoxyaniline (7.5 g, 40. mmol) was added to theabove residue in N,N-diisopropylethylamine (24 mL, 140 mmol). Theresulting mixture was stirred at 100° C. overnight. The reaction mixturewas cooled to room temperature, quenched with saturated aqueous NaHCO₃,and extracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified on silica gel (elutingwith 0-25% EtOAc in hexanes) to afford 7.5 g of the desired product.LCMS calculated for C₁₅H₁₅Cl₂F₂N₂O₂ [M+H]⁺ m/z: 363.0; Found: 363.0

Step 3:6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′-methyl-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one

The title compound was prepared using procedures analogous to thosedescribed for Example 1, Steps 3 to 6, withN-((4,6-dichloro-5-methylpyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline(Step 2) replacingN-((4,6-dichloropyridin-3-yl)methyl)-2,6-difluoro-3,5-dimethoxyanilinein Step 3. LCMS calculated for C₁₉H₁₈ClF₂N₂O₃ [M+H]⁺ m/z: 395.1; Found:395.1.

Step 4:N-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′-methyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide

The title compound was prepared using procedures analogous to thosedescribed for Example 2, Steps 2 to 6, with6′-chloro-2′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′-methyl-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′(2′H)-one(Step 3) replacing7-chloro-3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-onein Step 2. LCMS calculated for C₂₃H₂₄F₂N₃O₄ [M+H]⁺ m/z: 444.2; Found:444.2.

Example A FGFR Enzymatic Assay

The inhibitor potency of the exemplified compounds was measured in anenzyme assay that measures peptide phosphorylation using FRETmeasurements to detect product formation. Inhibitors were seriallydiluted in DMSO and a volume of 0.5 μL was transferred to the wells of a384-well plate. For FGFR3, a 10 μL volume of FGFR3 enzyme (Millipore)diluted in assay buffer (50 mM HEPES, 10 mM MgCl₂, 1 mM EGTA, 0.01%Tween-20, 5 mM DTT, pH 7.5) was added to the plate and pre-incubated fora time between 5-10 minutes and up to 4 hours. Appropriate controls(enzyme blank and enzyme with no inhibitor) were included on the plate.The assay was initiated by the addition of a 10 μL solution containingbiotinylated EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP(final concentrations of 500 nM and 140 μM respectively) in assay bufferto the wells. The plate was incubated at 25° C. for 1 hr. The reactionswere ended with the addition of 10 μL/well of quench solution (50 mMTris, 150 mM NaCl, 0.5 mg/mL BSA, pH 7.8; 30 mM EDTA with Perkin ElmerLance Reagents at 3.75 nM Eu-antibody PY20 and 180 nM APC-Streptavidin).The plate was allowed to equilibrate for ˜1 hr before scanning the wellson a PheraStar plate reader (BMG Labtech).

FGFR1, FGFR2, and FGFR4 are measured under equivalent conditions withthe following changes in enzyme and ATP concentrations: FGFR1, 0.02 nMand 210 uM respectively, FGFR2, 0.01 nM and 100 uM, respectively, andFGFR4, 0.04 nM and 600 uM respectively. The enzymes were purchased fromMillipore or Invitrogen.

GraphPad prism3 was used to analyze the data. The IC₅₀ values werederived by fitting the data to the equation for a sigmoidaldose-response with a variable slope. Y=Bottom+(Top−Bottom)/(1+10̂((LogIC₅₀−X)*HillSlope)) where X is the logarithm of concentration and Y isthe response. Compounds having an IC₅₀ of 1 μM or less are consideredactive.

The compounds of the invention were found to be selective inhibitors ofFGFR4 according to the FGFR Enzymatic Assay. Table 1 provides IC₅₀ datafor compounds of the invention assayed in the FGFR Enzymatic Assay afterdilution in assay buffer, added to the plate and pre-incubated for 4hours. The symbol: “+” indicates an IC₅₀ less than 10 nM; “++” indicatesan IC₅₀ greater than or equal to 10 nM but less than 30 nM; “+++”indicates an IC₅₀ greater than or equal to 30 nM but less than 200 nM;and “++++” indicates an IC₅₀ greater than or equal to 200 nM.

TABLE 1 FGFR1 FGFR2 FGFR3 FGFR4 Example No. IC50 (nM) IC50 (nM) IC50(nM) IC50 (nM) 1 +++ +++ +++ + 2 ++++ ++++ ++++ + 3 ++++ ++++ ++++ ++ 4++++ ++++ ++++ ++ 5 ++++ ++++ ++++ + 6 ++++ ++++ ++++ ++ 7 ++++ ++++++++ ++ 8 ++++ ++++ ++++ + 9 ++++ ++++ ++++ ++ 10 ++++ ++++ ++++ ++ 11++++ ++++ ++++ + 12 ++++ ++++ ++++ + 13 +++ ++++ +++ + 14 ++++ ++++++++ + 15 ++++ ++++ ++++ + 16 +++ +++ +++ ++ 17 ++++ ++++ ++++ ++ 18 ++++++ +++ + 19 ++++ ++++ ++++ + 20 ++++ ++++ ++++ + 21 ++++ ++++ ++++ + 22++++ ++++ ++++ ++ 23 ++++ +++ ++++ ++ 24 ++++ ++++ ++++ +++ 25 ++++ ++++++++ ++ 26 ++++ ++++ ++++ ++ 27 ++++ ++++ ++++ + 28 +++ +++ +++ + 29 ++++++ ++++ + 30 +++ +++ ++++ + 31 ++++ ++++ ++++ + 32 ++++ ++++ ++++ +++33 ++++ ++++ +++ + 34 ++++ ++++ ++++ + 35 ++++ ++++ ++++ + 36 ++++ ++++++++ + 37 ++++ ++++ ++++ ++

Table 2 provides IC₅₀ data for compounds of the invention assayed in theFGFR Enzymatic Assay after dilution in assay buffer, added to the plateand pre-incubated for 5 to 10 minutes. The symbol: “+” indicates an IC₅₀less than 10 nM; “++” indicates an IC₅₀ greater than or equal to 10 nMbut less than 30 nM; “+++” indicates an IC₅₀ greater than or equal to 30nM but less than 200 nM; and “++++” indicates an IC₅₀ greater than orequal to 200 nM.

TABLE 2 FGFR1 FGFR2 FGFR3 FGFR4 Example No. IC50 (nM) IC50 (nM) IC50(nM) IC50 (nM) 1 +++ ++++ ++++ +

Example B FGFR4 Cellular and In Vivo Assays

The FGFR4 inhibitory activity of the example compounds in cells,tissues, and/or animals can be demonstrated according to one or moreassays or models described in the art such as, for example, in French etal. “Targeting FGFR4 Inihibits Hepatocellular Carcinoma in PreclinicalMouse Models,” PLoS ONE, May 2012, Vol. 7, Issue 5, e36713, which isincorporated herein by reference in its entirety.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X¹ is CR¹⁰R¹¹ orNR⁷; X is N or CR⁶; R¹ is C₁₋₃ alkyl or C₁₋₃ haloalkyl; R² is H, halo,C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy; R³ is H, halo, C₁₋₃alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃ alkoxy; R⁴ is C₁₋₃ alkyl or C₁₋₃haloalkyl; R⁵ is H, halo, C₁₋₃ alkyl, C₁₋₃ haloalkyl, CN, or C₁₋₃alkoxy; R⁶is selected from H, halo, CN, OR^(a4), SR^(a4),C(O)NR^(c4)R^(d4), OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R⁶ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(10A); R⁷ is selected from H, C(O)NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R⁷ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR^(10A); L is —(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are eachindependently H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5 to 10 membered heteroaryl or4 to 10 membered heterocycloalkyl, wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, 5to 10 membered heteroaryl or 4 to 7 membered heterocycloalkyl isoptionally substituted with from 1 to 3 R¹⁷ groups; the subscript n is 1or 2; R⁸ is H or C₁₋₄ alkyl which is optionally substituted by halo, CN,OR^(a9), C(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), phenyl, C₃₋₇cycloalkyl, a 5-6 membered heteroaryl moiety having carbon and 1, 2, or3 heteroatoms independently selected from N, O and S, or a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R⁸ are each optionally substituted with 1 or 2 R¹⁹; R¹⁰ andR¹¹ are each independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, a 5-10membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-10 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl groups of R¹⁰ and R¹¹ areeach optionally substituted with 1, 2, 3, or 4 R^(10A); R^(10A), at eachoccurrence, is independently selected from halo, CN, NO₂, OR^(a4),SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), S(O)₂NR^(c4)R^(d4), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl group of R^(10A) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹; R^(a4), R^(b4), R^(c4), and R^(d4), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroup of R^(a4), R^(b4), R^(c4), and R^(d4) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹; alternatively, R^(c4) and R^(d4) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹; R^(e4), at eachoccurrence, is H or C₁₋₄ alkyl; alternatively, R¹⁰ and R¹¹ together withthe carbon atom to which they are attached form a 3-, 4-, 5-, 6-, or7-membered cycloalkyl group or a 4-, 5-, 6-, 7-, 8-, 9-, or 10-memberedheterocycloalkyl group; wherein said 3-, 4-, 5-, 6-, or 7-memberedcycloalkyl group and 4-, 5-, 6-, 7-, 8-, 9-, or 10-memberedheterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4R^(10A); R¹² is H or C₁₋₄ alkyl which is optionally substituted by R¹⁷;R¹⁷, at each occurrence, is independently selected from halo, CN, NO₂,OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), C(O)OR^(a7),OC(O)R^(b7), OC(O)NR^(c7)R^(d7), C(═NR^(e7))NR^(c7)R^(d7),NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), NR^(c7)S(O)R^(b7),NR^(c7)S(O)₂R^(b7), NR^(c7)S(O)₂NR^(c7)R^(d7), S(O)R^(b7),S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6membered heteroaryl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S, and a 4-7 memberedheterocycloalkyl moiety having carbon and 1, 2, or 3 heteroatomsindependently selected from N, O and S; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,and 4-7 membered heterocycloalkyl groups of R¹⁷ are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹; R^(a7), R^(b7), R^(c7), and R^(d7), at each occurrence, areindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, phenyl, C₃₋₆ cycloalkyl, a 5-6 membered heteroarylmoiety having carbon and 1, 2, or 3 heteroatoms independently selectedfrom N, O and S, and a 4-7 membered heterocycloalkyl moiety havingcarbon and 1, 2, or 3 heteroatoms independently selected from N, O andS; wherein said C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, phenyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkylgroups of R^(a7), R^(b7), R^(c7), and R^(d7) are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁹; alternatively, R^(c7) and R^(d7) together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group which is optionally substituted with 1, 2 or 3substituents independently selected from R¹⁹; R^(e7), at eachoccurrence, is independently H or C₁₋₄ alkyl; R¹⁹, at each occurrence,is independently selected from halo, CN, NO₂, OR^(a9), SR^(a9),C(O)R^(b9), C(O)NR^(c9)R^(d9), C(O)OR^(a9), OC(O)R^(b9),OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, and C₁₋₄ haloalkyl; R^(a9), R^(c9), and R^(d9),at each occurrence, are independently selected from H and C₁₋₄ alkyl;and R^(b9), at each occurrence, is independently C₁₋₄ alkyl.
 2. Thecompound of claim 1, having Formula (II):

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, having Formula (III):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, having Formula (IV):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R² is F and R⁵is F.
 6. The compound of claim 1, having Formula (V):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, having Formula (VI):

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, wherein R⁷ is C₁₋₆ alkyl, phenyl, 5- or 6-membered heteroaryl, C₃₋₆cycloalkyl or 4- to 6-membered heterocycloalkyl, each of which isoptionally substituted with from 1-2 members selected from halo, C₁₋₄alkyl, CN, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, phenyl, C₃₋₆ cycloalkyl, 5- or6-membered heteroaryl, or 4- to 6-membered heterocycloalkyl.
 9. Thecompound of claim 1, wherein R⁷ is methyl, ethyl, propyl, isopropyl,n-butyl, cyanomethyl, 2,2,2-trifluoroethyl, phenyl, 3-pyridyl,1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl,tetrahydrofuran-3-yl, 3,3-difluorocyclobutyl, 2-methoxyethyl,cyclopropyl, cyclopropylmethyl, 2,2-difluoroethyl, benzyl,3-fluorobenzyl, pyridin-3-ylmethyl, (1-methyl-1H-pyrazol-4-yl)methyl,(1-methyl-1H-pyrazol-3-yl)methyl, (teterahydrofuranyl-3-yl)methyl,2-fluoroethyl, 4-pyridyl, (piperidin-4-yl)methyl,(1-methylpiperidin-4-yl)methyl, (1-methoxycarbonylpiperidin-4-yl)methyl,(1-methyl sulfonylpiperidin-4-yl)methyl, tetrahydropyran-4-yl,cyclobutyl, cyclopentyl, isobutyl, 1-(cyclobutylmethyl), or4-methyl-N-isopropylpiperidine-1-carboxamide.
 10. The compound of claim1, wherein R⁷ is methyl, ethyl, propyl, isopropyl, n-butyl, cyanomethyl,2,2,2-trifluoroethyl, phenyl, 3-pyridyl, 1-methyl-1H-pyrazol-3-yl,1-methyl-1H-pyrazol-4-yl, tetrahydrofuran-3-yl, 3,3-difluorocyclobutyl,2-methoxyethyl, cyclopropyl, cyclopropylmethyl, 2,2-difluoroethyl,benzyl, 3-fluorobenzyl, pyridin-3-ylmethyl,(1-methyl-1H-pyrazol-4-yl)methyl, (1-methyl-1H-pyrazol-3-yl)methyl or(teterahydrofuranyl-3-yl)methyl.
 11. The compound of claim 1, wherein R⁷is ethyl, propyl, isopropyl, cyanomethyl, 2,2,2-trifluoroethyl,2,2-difluoroethyl, phenyl, 3-pyridyl, 1-methyl-1H-pyrazol-3-yl,tetrahydrofuran-3-yl, 3,3-difluorocyclobutyl, 2-methoxy ethyl,cyclopropyl, cyclopropylmethyl, 3-fluorobenzyl, pyridin-3-ylmethyl,(1-methyl-1H-pyrazol-4-yl)methyl, or (teterahydrofuranyl-3-yl)methyl.12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹⁰ is C₁₋₆ alkyl and R¹¹ is C₁₋₆ alkyl.
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹⁰ and R¹¹ are each methyl.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹⁰ and R¹¹ togetherwith the carbon atom to which they are attached form a 3-, 4-, 5-, 6-,or 7-membered cycloalkyl group.
 15. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹⁰ and R¹¹ togetherwith the carbon atom to which they are attached form a cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl group.
 16. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ and R¹¹together with the carbon atom to which they are attached form acyclopropyl or cyclopentyl.
 17. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹⁰ and R¹¹ togetherwith the carbon atom to which they are attached form a cyclopropylgroup.
 18. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹⁰ and R¹¹ together with the carbon atom to whichthey are attached form 4-, 5-, 6-, or 7-membered heterocycloalkyl group.19. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹⁰ and R¹¹ together with the carbon atom to which theyare attached form a tetrahydropyranyl group.
 20. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein L is—(CR¹³R¹⁴)_(n)—, wherein R¹³ and R¹⁴ are each independently H or C₁₋₄alkyl.
 21. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹³ and R¹⁴ are H.
 22. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein L is C₁₋₃ alkylene.23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L is —CH₂C(R¹³)(R¹⁴)— or —C(R¹³)(R¹⁴)CH₂—.
 24. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein L is —CH₂—.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R⁴ are C₁₋₆ alkyl.
 26. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ and R⁴ are methyl.
 27. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein X is CH or N.
 28. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein X is CH.
 29. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X is N.
 30. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein R¹² is H.
 31. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁸ is H.
 32. The compound of claim 1, wherein the compound isN-{[2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-6′-yl]methyl}acrylamide,or a pharmaceutically acceptable salt thereof.
 33. The compound of claim1, wherein the compound isN-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide,or a pharmaceutically acceptable salt thereof.
 34. The compound of claim1, wherein the compound isN-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide,or a pharmaceutically acceptable salt thereof.
 35. The compound of claim1, wherein the compound isN-((6′-(2,6-difluoro-3,5-dimethoxyphenyl)-7′-oxo-6′,7′-dihydro-5′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-2′-yl)methyl)acrylamide,or a pharmaceutically acceptable salt thereof.
 36. The compound of claim1, wherein the compound is selected from:N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((6′-(2,6-difluoro-3,5-dimethoxyphenyl)-7′-oxo-6′,7′-dihydro-5′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-2′-yl)methyl)acrylamide;N-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-phenyl-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;(S)—N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3,3-difluorocyclobutyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((1-cyclopropyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-propyl-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((1-(cyclopropylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(3-fluorobenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;(R)—N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((1-(cyanomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;andN-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;or a pharmaceutically acceptable salt thereof.
 37. The compound of claim1, wherein the compound is selected from:N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((7-(2,6-difluoro-3,5-dimethoxyphenyl)-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-2,7-naphthyridin-3-yl)methyl)acrylamide;N-((1-cyclobutyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-(pyridin-4-yl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-(2-fluoroethyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((1-cyclopentyl-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-isobutyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((1-(cyclobutylmethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;(S)—N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-1-((tetrahydrofuran-3-yl)methyl)-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-methylpiperidin-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;methyl4-((7-(acrylamidomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)piperidine-1-carboxylate;4-((7-(acrylamidomethyl)-3-(2,6-difluoro-3,5-dimethoxyphenyl)-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)methyl)-N-isopropylpiperidine-1-carboxamide;N-((3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;N-((3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-7-yl)methyl)acrylamide;andN-((2′-(2,6-difluoro-3,5-dimethoxyphenyl)-5′-methyl-3′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[2,7]naphthyridine]-6′-yl)methyl)acrylamide;or a pharmaceutically acceptable salt thereof.
 38. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier orexcipient.
 39. A method of inhibiting an FGFR4 enzyme comprisingcontacting said enzyme with a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 40. A method of treating cancer in a patientcomprising administering to said patient a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 41. A method of treating cancer in a patient comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof, incombination with another therapy or therapeutic agent.
 42. The method ofclaim 40, wherein said cancer is selected from hepatocellular cancer,bladder cancer, breast cancer, cervical cancer, colorectal cancer,endometrial cancer, gastric cancer, head and neck cancer, kidney cancer,liver cancer, lung cancer, ovarian cancer, prostate cancer, esophagealcancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skincancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adultT cell leukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin'sor non-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy celllymphoma, Burkett's lymphoma, glioblastoma, melanoma, and rhabdosarcoma.43. The method of claim 40, wherein said cancer is selected fromhepatocellular cancer, breast cancer, bladder cancer, colorectal cancer,melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer,testicular cancer, thyroid cancer, squamous cell carcinoma,glioblastoma, neuroblastoma, uterine cancer, and rhabdosarcoma.